Compounds and compositions as inhibitors of cannabinoid receptor 1 activity

ABSTRACT

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of Cannabinoid Receptor 1 (CB1).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 60/870,339, filed 15 Dec. 2006 and U.S.Provisional Patent Application No. 60/953,595, filed 2 Aug. 2007. Thefull disclosures of these applications are incorporated herein byreference in their entirety and for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention provides compounds, pharmaceutical compositions comprisingsuch compounds and methods of using such compounds to treat or preventdiseases or disorders associated with the activity of CannabinoidReceptor 1 (CB1).

2. Background

The cannabinoids are psychoactive ingredients of marijuana, principallydelta-9-tetrahydrocannabinol. Two cannabinoid receptors have beencloned, CB1 and CB2. CB1 is predominantly expressed in the centralnervous system whereas CB2 is expressed in peripheral tissues,principally in the immune system. Both receptors are members of theG-protein coupled class and their inhibition is linked to adenylatecyclase activity.

The novel compounds of this invention inhibit the activity of CB1 andare, therefore, expected to be useful in the treatment of CB1-associateddiseases or disorders such as, but not limited to, psychosis, memorydeficit, cognitive disorders, migraine, neuropathy, neuroinflammatorydisorders, cerebral vascular accidents, head trauma, anxiety disorders,substance abuse (such as smoking cessation), stress, epilepsy,Parkinson's disease, schizophrenia, osteoporosis, constipation, chronicintestinal pseudo-obstruction, cirrhosis of the liver, asthma, obesity,and other eating disorders associated with excessive food intake.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of Formula I:

in which:

Y₁ is selected from N and CR₁₁;

Y₂ is selected from N and CR₈;

Z₁ is selected from S, O, NH, CH—NO₂, NS(O)₂NH₂, NC(O)NH₂, NS(O)₂CH₃,N(OH) and N(CN); or C=Z₁ of Formula I is replaced with CH₂ or S(O)₂;

Z₂ is selected from O, —CH₂CHR_(1a)—, —OCHR_(1a)—, —CR_(1a)R_(1b) and—NR_(1a);

R_(1a) is selected from hydrogen, cyano, C₁₋₆alkyl,cyano-substituted-C₁₋₆alkyl, C₂₋₆alkenyl, —X₁R₁₂, —X₁NR₁₃S(O)₂R₁₃,—X₁OS(O)₂R₁₃, —X₁NR₁₃X₁OR₁₃, —X₁OR₁₃, —X₁C(O)OR₁₃, —X₁S(O)₂R₁₂,—X₁S(O)₂NR₁₃C(O)R₁₃, —X₁S(O)₂R₁₃, —X₁C(O)R₁₂, —X₁NR₁₃R₁₃,—X₁S(O)₂NR₁₃R₁₃, —X₁OC(O)NR₁₃R₁₃, —X₁C(O)NR₁₂R₁₃, —X₁NR₁₃X₁C(O)NR₁₂,—X₁NR₁₃X₁C(O)NR₁₃R₁₃, —X₁C(O)NR₁₃X₁C(O)OR₁₃, —X₁C(O)NR₁₃X₁NR₁₃R₁₃,—X₁C(O)NR₁₃X₁OR₁₃ and —X₁C(O)NR₁₃R₁₃; wherein R₁₂ is selected fromC₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl and C₃₋₁₀heterocycloalkyl;wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁₂ isoptionally substituted by 1 to 3 radicals independently selected fromhydroxy, bis-hydroxy-C₁₋₆alkyl-amino, C₁₋₆alkyl-amino, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-sulphoxy, C₁₋₆alkyl-carboxy,C₁₋₆alkyl-sulfonyl, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, C₃₋₁₂cycloalkyl, C₃₋₁₀heterocycloalkyl,C₅₋₁₀heteroaryl and C₆₋₁₀aryl optionally substituted with 1 to 3 haloradicals; wherein said cycloalkyl, heterocycloalkyl, heteroaryl and arylsubstituents of R₁₂ can be further optionally substituted with 1 to 3C₁₋₆alkyl radicals; wherein each R₁₃ is independently selected fromhydrogen, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₆₋₁₀aryl,C₃₋₁₀heterocycloalkyl; wherein said aryl or heterocycloalkyl of R₁₃ isoptionally substituted with a group selected from C₁₋₆alkyl andC₁₋₆alkoxy; wherein each X₁ is independently selected from a bond andC₁₋₄alkylene; wherein any alkyl of R₁ is optionally substituted withcyano;

R_(1b) is selected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl;

R_(2a) is selected from hydrogen, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl,C₆₋₁₀aryl, —X₂NR₁₄X₂NR₁₄R₁₄, —X₂NR₁₄C(O)X₂NR₁₄C(O)OR₁₄, —X₂NR₁₄X₂R₁₅,—X₂OC(O)NR₁₄R₁₄, —X₂OC(O)NR₁₄R₁₅, —X₂NR₁₄R₁₄, —X₂NR₁₄S(O)₂R₁₄,—X₂NR₁₄S(O)₂R₁₅, —X₂S(O)₀₋₂R₁₅, —X₂NR₁₄C(O)R₁₄, —X₂NR₁₄C(O)R₁₅,—X₂NR₁₄C(O)X₂NR₁₄R₁₄, —X₂OSi(R₁₄)₃, —X₂OC(O)NR₁₄R₁₅, —X₂C(O)OR₁₄,—X₂OR₁₄, —X₂OX₂R₁₅, —X₂R₁₅ and —X₂C(O)R₁₅; wherein each R₁₄ isindependently selected from hydrogen and C₁₋₆alkyl; R₁₅ is selected fromcyano, C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl andC₃₋₁₀heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₁₅ is optionally substituted by 1 to 3 radicalsindependently selected from hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkyl-sulphoxy, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, —X₃NR₁₆R₁₆, —X₃ONR₁₆R₁₆, —X₃OR₁₆,—X₃S(O)₂R₁₆, —X₃NR₁₆C(O)OR₁₆, —X₃NR₁₆S(O)₀₋₂R₁₆, —X₃R₁₆, —X₃C(O)OR₁₆,—X₃C(O)NR₁₆R₁₆, —X₃OC(O)NR₁₆R₁₆, —X₃S(O)₀₋₂NR₁₆R₁₆, —X₃C(O)R₁₆,C₆₋₁₀aryl and C₅₋₁₀heteroaryl; wherein said aryl and heteroarylsubstituents of R₁₅ are optionally substituted with 1 to 3 haloradicals; each X₂ and X₃ are independently selected from a bond andC₁₋₄alkylene; and each R₁₆ is independently selected from hydrogen,C₁₋₆alkyl, C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₈cycloalkyl andC₃₋₁₂heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl orheterocycloalkyl of R₁₆ is optionally substituted by 1 to 3 radicalsindependently selected from halo, cyano, C₁₋₆alkyl,C₁₋₆alkyl-carbonyl-amino and C₁₋₆alkoxy;

R_(2b) is selected from hydrogen and C₁₋₆alkyl; or R_(2a) and R_(2b)together with the carbon atom to which R_(2a) and R_(2b) are attachedform carbonyl;

R₃, R₅, R₆ and R₇ are each independently selected from hydrogen, haloand amino;

R₄ is selected from hydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy,hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy,cyano-substituted-C₁₋₆alkyl, cyano-substituted-C₁₋₆alkoxy, —OX₅R_(4a)and —OX₅R_(4a); wherein X₅ is selected from a bond and C₁₋₄alkylene;R_(4a) is selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl andC₅₋₁₀heteroaryl; wherein any cycloalkyl, aryl or heteroaryl of R_(4a) isoptionally substituted with 1 to 3 radicals independently selected fromhalo, cyano, amino, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl,halo-substituted-C₁₋₆alkoxy, hydroxy-substituted-C₁₋₆alkyl,hydroxy-substituted-C₁₋₆alkoxy, cyano-substituted-C₁₋₆alkyl andcyano-substituted-C₁₋₆alkoxy;

R₈, R₉, R₁₁ and R_(12a) are each independently selected from hydrogen,halo, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl andhalo-substituted-C₁₋₆alkoxy;

R₁₀ is selected from halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —X₄OR₁₇,—X₄S(O)₀₋₂R₁₇ and —X₄R₁₇; wherein X₄ is selected from a bond and C₁₇alkylene; and R₁₇ is selected from C₆₋₁₀aryl and C₅₋₁₀hetyeroaryl;wherein R₁₇ is optionally substituted with 1 to 3 halo radicals; and thepharmaceutically acceptable salts, hydrates, solvates and isomersthereof.

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound of Formula I or a N-oxidederivative, individual isomers and mixture of isomers thereof; or apharmaceutically acceptable salt thereof, in admixture with one or moresuitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which modulation of CB1 activity can prevent,inhibit or ameliorate the pathology and/or symptomology of the diseases,which method comprises administering to the animal a therapeuticallyeffective amount of a compound of Formula I or a N-oxide derivative,individual isomers and mixture of isomers thereof, or a pharmaceuticallyacceptable salt thereof.

In a fourth aspect, the present invention provides the use of a compoundof Formula I in the manufacture of a medicament for treating a diseasein an animal in which CB1 activity contributes to the pathology and/orsymptomology of the disease.

In a fifth aspect, the present invention provides a process forpreparing compounds of Formula I and the N-oxide derivatives, prodrugderivatives, protected derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl and alkoxy, can be eitherstraight-chained or branched. C₁₋₆alkoxy includes, methoxy, ethoxy, andthe like. Halo-substituted alkyl includes trifluoromethyl,pentafluoroethyl, and the like.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, aryl can be phenylor naphthyl, preferably phenyl. “Arylene” means a divalent radicalderived from an aryl group. “Heteroaryl” is as defined for aryl whereone or more of the ring members are a heteroatom selected from —O—, —N═,—NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—, wherein R is hydrogen, C₁₋₄alkylor a nitrogen protecting group. For example C₁₋₁₀heteroaryl includespyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl,benzopyranyl, benzothiopyranyl, benzo[1,3]dioxole, imidazolyl,benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl,tetrazolyl, pyrazolyl, thienyl, 1H-pyridin-2-onyl,6-oxo-1,6-dihydro-pyridin-3-yl, etc. “C₆₋₁₀arylC₀₋₄alkyl” means an arylas described above connected via a alkylene grouping. For example,C₆₋₁₀arylC₀₋₄alkyl includes phenethyl, benzyl, etc. Heteroaryl alsoincludes the N-oxide derivatives, for example, pyridine-N-oxidederivatives with the following structure:

“Cycloalkyl” means a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing the numberof ring atoms indicated. For example, C₃₋₁₀cycloalkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the ring carbons indicated, are replaced bya moiety selected from —O—, —N═, —NR—, —C(O)—, —S—, —S(O)— or —S(O)₂—,wherein R is hydrogen, C₁₋₄alkyl or a nitrogen protecting group. Forexample, C₃₋₈heterocycloalkyl as used in this application to describecompounds of the invention includes morpholino, pyrrolidinyl,piperazinyl, piperidinyl, piperidinylone,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo-pyrrolidin-1-yl,2-oxo-piperidin-1-yl, etc.

“Halogen” (or halo) preferably represents chloro or fluoro, but can alsobe bromo or iodo.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides compounds, compositions and methods forthe treatment of diseases in which inhibition of CB1 activity canprevent, inhibit or ameliorate the pathology and/or symptomology of thediseases, which method comprises administering to the animal atherapeutically effective amount of a compound of Formula I.

In one embodiment, with regard to compounds of Formula I, R_(1a) isselected from cyano, methyl-carbonyl-amino-sulfonyl-ethyl,pyrrolidin-2-onyl-ethyl, imidazolyl-ethyl, oxazolidin-2-only-ethyl,1-pyrazolyl-ethyl, cyano-methyl, 4′-(4-chlorophenoxy)phenyl,1,3-dioxanyl-ethyl, allyl, phenyl, pyrazinyl,piperazinyl-sulfonyl-ethyl, azetidinyl-sulfonyl-ethyl,morpholino-sulfonyl-ethyl, pyrrolidinyl-sulfonyl-ethyl,pyrrolidinyl-propyl, pyrrolidinyl-ethyl, piperazinyl-propyl,piperidinyl-sulfonyl-ethyl, pyridazinyl,(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl, isoxazolyl,piperidinyl-carbonyl-methyl,3-(N,N-bis(4-methoxyphenyl)sulfamoyl)propyl, methyl-phenyl-sulfonyl,cyanomethyl, 2-oxo-2-(piperidin-1-ylamino)ethyl,propyl-amino-carbonyl-methyl, 2-(carboxymethylamino)-2-oxoethyl),bis-hydroxyethyl-amino-sulfonyl-ethyl,carboxy-methyl-amino-carbonyl-methyl, amino-carbonyl-ethyl,amino-sulfonyl-ethyl, amino-sulfonyl-propyl, methyl-amino-ethyl,piperidinyl-ethyl, piperazinyl-ethyl, methyl-sulfonyl-ethyl,carboxy-methyl, tetrazole-methyl, benzyl, 1,2,4-oxadiazole,1,2,4-oxadiazole-methyl, 1,2,4-oxadiazole-ethyl, isoxazole-methyl,2-(2-hydroxyethylamino)-2-oxoethyl,dimethylamino-ethyl-amino-carbonyl-methyl, hydroxyl-ethyl,methoxy-ethyl, hydroxyl-ethyl-amino-ethyl, morpholino-ethyl,methyl-piperazinyl-ethyl, 2-(carbamoyloxy)ethyl,methyl-sulfonyl-oxy-ethyl, morpholino-carbonyl-methyl,methyl-sulfonyl-piperazinyl-ethyl, 2-morpholinoethyl, amino-ethyl,2-(3,3-dimethylureido)ethyl, morpholino-carbonyl-amino-ethyl,methyl-sulfonyl-amino-ethyl, pyridinyl-methyl, hydroxyl-propyl,2-(2,6-dimethylmorpholino)ethyl, 2-(2-methylmorpholino)ethyl,methyl-sulfonyl-propyl and morpholino-propyl; wherein said ring systemsof R_(1a) are optionally substituted with 1 to 3 radicals independentlyselected from halo, trifluoromethyl, methyl, bis-hydroxy-ethyl-amino,t-butyl, t-butoxy-carbonyl, hydroxy, methyl-sulfonyl, amino-sulfonyl,diethyl-amino, morpholino, cyclohexyl, pyridinyl, piperidinyl,pyrrolidinyl, piperazinyl optionally substituted with ethyl ormethyl-sulfonyl, methoxy-carbonyl and methoxy; and R_(1b) is selectedfrom hydrogen and allyl.

In another embodiment, R_(2a) is selected from(4-(azepan-1-yl-methyl)-1H-1,2,3-triazol-1-yl)methyl,diethyl-amino-pyrrolidinyl-methyl,N,N-methyl-(t-butoxy-carbonyl)-amino-pyrrolidinyl-methyl,(4-(5-cyanopyridin-2-yl)piperazin-1-yl)methyl,5-cyanopyridinyl-oxy-methyl,(4-(6-methoxypyridin-3-yl)-3-oxopiperazin-1-yl)methyl,(4-(6-methoxypyridin-2-yl)-3-oxopiperazin-1-yl)methyl,(4-(6-methoxypyridin-2-yl)piperazin-1-yl)methyl,4-t-butoxy-carbonyl-2-oxopiperazin-1-yl)methyl,(4-(4-fluoropyridin-2-yl)piperazin-1-yl)methyl,5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-tetrazol-2-yl-methyl,5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-tetrazol-1-yl-methyl,t-butoxy-carbonyl-piperidinyl-methyl,4-(4-cyanophenyl)-1H-1,2,3-triazol-1-yl,4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl,4-((tetrahydrofuran-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl,5-phenyl-2H-tetrazol-2-yl, 4-oxadiazolyl-piperidinyl-methyl,4-(benzyloxycarbonyl)-2-oxopiperazin-1-yl,4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl,4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-1-yl,4-ethoxy-1H-1,2,3-triazol-1-yl,4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazol-1-yl,5-(2-ethoxy-2-oxoethyl)-2H-tetrazol-2-yl,5-(hydroxy-ethyl)-2H-tetrazol-2-yl,(4-(piperidin-1-ylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl,1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,3-triazol-4-yl,5-(6-methoxy-pyridin-3-yl)-2H-tetrazol-2-yl-methyl,5-(pyridin-3-yl)-2H-tetrazol-2-yl-methyl,(3-(tetrahydrofuran-3-yl)isoxazol-5-yl)methyl,5-(morpholino-ethyl)-2H-tetrazol-2-yl,(4-(ethoxy-carbonyl)-1H-1,2,3-triazol-1-yl)methyl,ethyl-sulfonyl-piperazinyl-methyl,(4-(ethyl-sulfonyl-methyl)-1H-1,2,3-triazol-1-yl)methyl, methyl,methyl-piperazinyl-methyl, dimethyl-aminoethyl-amino-methyl,amino-methyl, methyl-sulfonyl-amino-methyl, methoxy-carbonyl,ethoxy-carbonyl, phenyl, hydroxy-methyl, methoxy-methyl,morpholino-methyl, phenyl-sulfonyl-methyl,dimethyl-amino-carbonyl-piperazinyl-methyl,dimethylamino-sulfonyl-piperazinyl-methyl, piperidinyl-methyl,t-butyl-carbamoyl-methyl, t-butoxy-carbonyl-amino-piperidinyl-methyl,phenyl-sulfonyl-amino-methyl,(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl,(4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl, chloromethyl,morpholino-ethyl-piperazinyl-methyl,t-butoxy-carbonyl-amino-pyrrolidinyl-methyl, thiomorpholinomethyl,amino-pyrrolidinyl-methyl, piperazinyl-methyl, benzyl-amino-methyl,benzyloxy-methyl, 4-fluoro-benzyloxy-methyl,2,4-difluoro-benzyloxy-methyl,(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl,dimethyl-amino-methyl, morpholino-ureido-methyl,(4-methyl-sulfonyl-amino-methyl-1H-1,2,3-triazol-1-yl)methyl,morpholino-carbonyl, propargyl-amino-methyl, phenyl-sulfanyl-methyl,pyridinyl-methyl-amino-methyl,(4-(dimethyl-amino-methyl)-1H-1,2,3-triazol-1-yl)methyl,pyrimidinyl-piperazinyl-methyl, phenyl-pyrazonyl-methyl,(2-(tert-butoxycarbonylamino)-3-methylbutanamido)methyl,(2-amino-3-methylbutanamido)methyl,(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl,(isopropyl-carbamoyloxy)methyl, ((t-butyl)(dimethyl)siloxy)-methyl,imidazoly-propyl-amino-methyl,(3-(2-oxopyrrolidin-1-yl)propylamino)methyl,pyrrolidinyl-ethyl-aminomethyl, pyrrolidinyl-propyl-aminomethyl,(cyclohexyl-carbamoyloxy)methyl,(benzo[d][1,3]dioxol-5-ylcarbamoyloxy)methyl,(1,3-dioxoisoindolin-2-yl)methyl, methyl-carbonyl-amino-methyl,(3-ethylureido)methyl, (tetrahydro-2H-pyran-2-yloxy)methyl,t-butoxy-carbonyl-piperazinyl-methyl, pyridinyl-ethyl-amino-methyl,methyl-carbonyl-piperazinyl-methyl, pyridinyl-piperazinyl-methyl,methoxy-carbonyl-piperazinyl-methyl, ethoxy-carbonyl-piperazinyl-methyl,piperidinyl-methyl-2H-tetrazol-2-yl, 5-chloro-pyridinyl-2-oxy-methyl,4-phenyl-piperidinyl-methyl, 4-(pyrimidin-2-yl)-piperidinyl-methyl,(5-(pyrazin-2-yl)-2H-tetrazol-2-yl)methyl,(5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl,(5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl,5-(6-methyl-pyridin-3-yl)-1H-tetrazol-1-yl)methyl,(5-(pyrimidin-2-yl)-2H-tetrazol-2-yl)methyl,(4-(pyrazin-2-yl)piperazin-1-yl)methyl,4-(pyridin-2-yl)-piperidinyl-methyl,3-t-butoxy-carbonyl-amino-pyrrolidinyl-methyl,(5-(6-chloropyridin-3-yl)-2H-tetrazol-2-yl)methyl,piperidinyl-methyl-1H-1,2,3-triazol-1-yl-methyl,4-methyl-piperidinyl-methyl-1H-1,2,3-triazol-1-yl-methyl,4-isopropyl-amino-methyl-1H-1,2,3-triazol-1-yl-methyl,4-phenyl-1H-imidazol-1-yl, 1H-1,2,3-triazol-1-yl-methyl,5-(ethoxy-carbonyl)-2H-tetrazol-2-yl,(4-(3,5-dimethylphenyl)-3-oxopiperazin-1-yl)methyl,(5-(imidazo[1,2-a]pyridin-6-yl)-2H-tetrazol-2-yl)methyl,4-hydroxy-4-phenyl-piperidinyl-methyl,4-hydroxy-4-(4-chloro-phenyl)-piperidinyl-methyl,(5-methyl-2-oxopyridin-1(2H)-yl)methyl, 4-methyl-pyridinyl-2-oxy-methyl,4-ethoxy-1H-1,2,3-triazol-1-yl-methyl,morpholino-methyl-1H-1,2,3-triazol-1-yl-methyl,diethyl-amino-ethyl-1H-1,2,3-triazol-1-yl-methyl,piperidinyl-ethyl-1H-1,2,3-triazol-1-yl-methyl,piperidinyl-methyl-1H-1,2,3-triazol-1-yl-methyl,diethyl-amino-ethyl-1H-1,2,3-triazol-1-yl-methyl,isopropyl-ethyl-1H-1,2,3-triazol-1-yl-methyl,(4-((3-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl,(4-((4-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl,acetamido-phenyl-1H-1,2,3-triazol-1-yl-methyl,acetyl-1H-1,2,3-triazol-1-yl-methyl,cyclohexyl-methyl-1H-1,2,3-triazol-1-yl-methyl,thienyl-1H-1,2,3-triazol-1-yl-methyl,(2-oxo-4-(pyridin-2-yl)piperazin-1-yl)methyl,(4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl,(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl,(4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)methyl,ethoxy-carbonyl-piperidinyl-methyl andisobutoxy-carbonyl-piperazinyl-methyl; and R_(2b) is selected fromhydrogen and methyl; or R_(2a) and R_(2b) together with the carbon atomto which R_(2a) and R_(2b) are attached form carbonyl.

In another embodiment, R₃, R₅, R₆ and R₇ are each independently selectedfrom hydrogen, halo and amino.

In another embodiment, R₄ is selected from: hydrogen; trifluoro-methyl;halo; hydroxy; cyano-methoxy; dimethyl-amino-propyl; cyano;cyclopropyl-methoxy; pyrazinyl-oxy optionally substituted with amino;pyridinyl-oxy; pyrimidinyl-oxy; benzoxy; phenoxy optionally substitutedwith methyl or cyano; ethoxy; tetrazolyl-methoxy optionally substitutedwith methyl; pyridazinyl-oxy; pyrazinyl-oxy; hydroxy-ethoxy; andmethoxy.

In another embodiment, R₈, R₉, R₁₁ and R_(12a) are each independentlyselected from hydrogen, halo, trifluoromethyl and methyl.

In another embodiment, R₁₀ is selected from halo, cyano, methoxy,trifluoromethyl, pyridinyl-oxy, benzoyl, phenoxy, benzyl,pyridazinyl-oxy, phenyl-sulfonyl and pyrimidinyl-oxy; wherein saidpyridinyl-oxy, phenyl-sulfonyl, phenoxy, benzoyl, benzyl,pyridazinyl-oxy and pyrimidinyl-oxy can be optionally substituted with 1to 3 halo radicals.

In another embodiment are compounds selected from:1-[4-(4-Chloro-phenoxy)-phenyl]-5-phenyl-pyrrolidin-2-one;5-(4-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one;1-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one;(S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one;5-(2-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one;6-(4-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-piperidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(R)-1-(4-(4-chlorophenoxy)phenyl)-5-phenylimidazolidine-2,4-dione;(S)-1-(4-(4-chlorophenoxy)phenyl)-5-phenylimidazolidine-2,4-dione;1-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-fluoro-5-trifluoromethyl-phenyl)-pyrrolidin-2-one;(S)-3-[4-(4-Chloro-benzoyl)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one;(S)-3-(4-Bromo-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one;(S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-fluoro-5-trifluoromethyl-phenyl)-oxazolidin-2-one;(S)-3-(4-Benzyl-phenyl)-4-(3-trifluoromethyl-phenyl)-4-oxazolidin-2-one;1-[4-(4-Chloro-phenoxy)-phenyl]-3-methyl-5-(S)-phenyl-imidazolidine-2,4-dione;3-[4-(4-chloro-phenoxy)-phenyl]-1-methyl-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one;ethyl2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetate;(S)-ethyl2-(3-(4-(4-chlorophenoxy)phenyl)-2,5-dioxo-4-phenylimidazolidin-1-yl)acetate;(R)-1-(4-(4-chlorophenoxy)phenyl)-3-methyl-5-phenylimidazolidine-2,4-dione;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-methyl-4-phenyloxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4,5-diphenyloxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4,5-diphenyloxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-methyl-4-phenyloxazolidin-2-one;(S)-3-(4-(4-chlorophenoxy)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one;(4S,5R)-ethyl3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidine-5-carboxylate;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(methoxymethyl)-4-phenyloxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-phenyloxazolidin-2-one;((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methylisopropylcarbamate;((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methylcyclohexylmethylcarbamate;((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methylbenzo[d][1,3]dioxol-5-ylcarbamate;2-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-phenyl-oxazolidin-2-one;N-((4S,5S)-3-(4-(4-chloro-phenoxy)-phenyl)-2-oxo-4-phenyl-oxazolidin-5-ylmethyl)-methanesulfonamide;N-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methyl)acetamide;1-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methyl)-3-ethylurea;(4S,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4-(4-chloro-phenoxy)-phenyl)-4-phenyl-oxazolidin-2-one;(4S,5R)-ethyl3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidine-5-carboxylate;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one;(S)-4-(4-(4-chlorophenoxy)phenyl)-5-(3-fluorophenyl)morpholin-3-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-carboxylate;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-5-(hydroxymethyl)oxazolidin-2-one;(2R,3S)-ethyl4-(4-(4-chlorophenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)-5-oxomorpholine-2-carboxylate;(2S,3S)-ethyl4-(4-(4-chlorophenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)-5-oxomorpholine-2-carboxylate;(4S,5R)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)-3-(4-methoxyphenyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-hydroxyphenyl)oxazolidin-2-one;(5S,6R)-4-(4-(4-chlorophenoxy)phenyl)-6-((benzyloxy)methyl)-5-(3,5-difluorophenyl)morpholin-3-one;(5S,6R)-4-(4-(4-chlorophenoxy)phenyl)-5-(3,5-difluorophenyl)-6-(hydroxymethyl)morpholin-3-one);(4S,5S)-5-((2-(dimethylamino)ethylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-5-((2-(pyrrolidin-1-yl)ethylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-5-((3-(pyrrolidin-2-one)-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-5-((3-(1H-imidazol-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-5-((3-(pyrrolidin-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-5-((3-(1H-imidazol-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;tert-butyl4-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;(4S,5S)-5-((3-(pyridin-3-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5R)-3-(4-(trifluoromethyl)phenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5S)-5-((4-acetylpiperazin-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-5-((2-(1H-imidazol-5-yl)ethylamino)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5R)-3-(4-chloro-3-methylphenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5R)-3-(4-chloro-3-fluorophenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;tert-butyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;tert-butyl4-(((4S,5S)-3-(4-chloro-3-methylphenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;tert-butyl4-(((4S,5S)-3-(4-chloro-3-(trifluoromethyl)phenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;(4S,5R)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5R)-5-((benzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one;tert-Butyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;Methyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;Ethyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;isobutyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;4-((4S,5R)-4-(3-methoxyphenyl)-2-oxo-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-3-yl)benzonitrile;4-((4S,5R)-5-((4-fluorobenzyloxy)methyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-3-yl)benzonitrile;(4S,5R)-5-((4-fluorobenzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-fluorophenyl)oxazolidin-2-one;(4S,5R)-5-((4-fluorobenzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one;(4S,5R)-5-((2,4-difluorobenzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one;5-((4S,5R)-5-((4-methoxybenzyloxy)methyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-3-yl)pyridine-2-carbonitrile;(4S,5R)-3-(5-(4-chlorophenoxy)pyrazin-2-yl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((3-phenyl-1H-pyrazol-1-yl)methyl)oxazolidin-2-one;tert-butyl(R)-1-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methylcarbamoyl)-2-methylpropylcarbamate;(2R)—N-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methyl)-2-amino-3-methylbutanamide;(4S,5S)-5-((3-(pyrrolidin-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-methylpiperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-(3-fluorophenyl)oxazolidin-2-one;((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methylcyclohexylcarbamate;((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methylisopropylcarbamate;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-((dimethylamino)methyl)-4-(3-fluorophenyl)oxazolidin-2-one;N-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)morpholine-4-carboxamide;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(morpholine-4-carbonyl)-4-phenyl-oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((prop-2-ynylamino)methyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((phenylthio)methyl)oxazolidin-2-one;(4S,5S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-fluoro-phenyl)-5-{[(pyridin-3-ylmethyl)-amino]-methyl}-oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3,5-difluoro-phenyl)-5-morpholin-4-ylmethyl-oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-5-((4-methylpiperazin-1-yl)methyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((phenylsulfonyl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(chloromethyl)-4-(3-fluorophenyl)oxazolidin-2-one;(4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-(2-morpholinoethyl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5R)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-3-p-tolyloxazolidin-2-one;(4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one;(4S,5R)-5-((benzyloxy)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-(morpholin-4-ylmethyl)oxazolidin-2-one;(4S,5S)-5-((3-(1H-imidazol-1-yl)propylamino)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;tert-butyl(R)-1-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)pyrrolidin-3-ylcarbamate;tert-butyl4-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;(4S,5R)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(thiomorpholinomethyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(((R)-3-aminopyrrolidin-1-yl)methyl)-4-(3-fluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-5-((benzylamino)methyl)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one;(4S,5R)-3-(4-chlorophenyl)-4-(2,3-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;(4S,5R)-5-((benzyloxy)methyl)-3-(4-chloro-3-fluorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;4-(((4S,5S)-3-(3,4-dichlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide;4-(((4S,5S)-3-(4-trifluoromethylphenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-N,N-dimethylpiperazine-1-sulfamide;(4S,5S)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)-5-((piperidin-1-yl)methyl)oxazolidin-2-one;((4S,5R)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyltert-butylcarbamate;(4S,5R)-5-((benzyloxy)methyl)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one;tert-butyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperidin-4-ylcarbamate;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5R)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one;((4S,5R)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methylcyclohexylcarbamate;N-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)benzenesulfonamide;4-((4S,5R)-5-((benzyloxy)methyl)-4-(3-fluorophenyl)-2-oxooxazolidin-3-yl)benzonitrile;(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one;(4S,5R)-5-((4-fluorobenzyloxy)methyl)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one;Ethyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;(4S,5R)-5-((4-methylbenyzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one;(4S,5S)-3-(5-(4-chlorophenoxy)pyrazin-2-yl)-4-(3-(trifluoromethyl)phenyl)-5-(morpholinomethyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;Ethyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate;(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;N-((1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methansulfonamide;(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetonitrile;3-(4-(4-chlorophenoxy)phenyl)-1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-[4-(4-Chloro-phenoxy)-phenyl]-1-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one;(S)-3-[4-(6-Chloro-pyridazin-3-yloxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one;(S)-3-(4-(5-chloropyridin-2-yloxy)phenyl)-4-(3-(trifluoromethyl)-phenyl)oxazolidin-2-one;(S)-1-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one;(R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one;(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(4-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one;(S)-1-(6-(4-chlorophenoxy)pyridin-3-yl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one;(S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one;(S)-1,3-Bis-[4-(4-chloro-phenoxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-ylidene-cyanamide;(S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-ylidene-cyanamide;(S)-2-(3-(5-(4-chlorophenoxy)pyrazin-2-yl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethanesulfonamide;(S)-3-[4-(4-Chloro-phenoxy)-phenyl]-1-(2-methanesulfonyl-ethyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one;(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethanesulfonamide;2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)aceticacid;1-((1H-tetrazol-5-yl)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-propylacetamide;2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(piperidin-1-yl)acetamide;2-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetamido)aceticacid;2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(2-hydroxyethyl)acetamide;2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(2-(dimethylamino)ethyl)acetamide;3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one;1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-imine;1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidine-2-thione;2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylmethanesulfonate;1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-oneoxime;3-(4-(4-chlorophenoxy)phenyl)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(2-hydroxyethylamino)ethyl)-4-(3-(trifluoromethyl)-phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-morpholinoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylcarbamate;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylamino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(piperidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(piperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one;(4R,5S)-methyl1-(4-(4-chlorophenoxy)phenyl)-2-oxo-5-phenylimidazolidine-4-carboxylate;1-(4-chlorobenzyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;1-benzyl-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(3-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(4-methoxyphenyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-morpholino-2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-((2S,6R)-2,6-dimethylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;1-(2-aminoethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)-1,1-dimethylurea;N-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)morpholine-4-carboxamide;N-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)methanesulfonamide;3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-2-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-3-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-4-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;(R)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;3-(4-(4-chlorophenoxy)phenyl)-1-(2-((R)-2-methylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-((S)-2-methylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(3-(methylsulfonyl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;3-(4-(4-chlorophenoxy)phenyl)-1-(3-morpholinopropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-morpholinoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-((S)-2-methylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;N-(3-(4-(4-chlorophenoxy)phenyl)-1-(3-(methylsulfonyl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;(R)-1-(4-(4-chlorophenoxy)phenyl)-5-phenylpyrrolidin-2-one;(R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one;(R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)pyrrolidin-2-one;(R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-methoxyphenyl)pyrrolidin-2-one;(R)-1-(4-(4-chlorophenylsulfonyl)phenyl)-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one;(R)-1-(4-(4-chlorophenylsulfonyl)phenyl)-5-(3-methoxyphenyl)pyrrolidin-2-one;(R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one;(R)-1-(4-(4-chlorophenoxy)phenyl)-2-(3-(trifluoromethyl)phenyl)pyrrolidine;(R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)pyrrolidin-2-one;(R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-one;(R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(4-(4-chlorophenylsulfonyl)phenyl)pyrrolidin-2-one;(R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-hydroxyphenyl)pyrrolidin-2-one;(R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-cyanomethoxyphenyl)pyrrolidin-2-one;(R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)pyrrolidin-2-one;(3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-3-allyl-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one;(3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-3-allyl-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one;(R)-1-(4-(4-chlorophenoxy)phenyl)-3,3-diallyl-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one;(R)-5-(3-((1-methyl-1H-tetrazol-5-yl)methoxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-one;(R)-5-(3-((2-methyl-2H-tetrazol-5-yl)methoxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-one;(3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-hydroxyethyl)pyrrolidin-2-one;(3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-hydroxyethyl)pyrrolidin-2-one;(R)-2-(3-(1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-yl)phenoxy)ethanol;(3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(3-hydroxypropyl)pyrrolidin-2-one;(3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(3-hydroxypropyl)pyrrolidin-2-one;(R)-1-(4-chlorophenyl)-5-(3-methoxyphenyl)pyrrolidin-2-one;(R)-1-(4-chlorophenyl)-5-(3-(pyridazin-3-yloxy)phenyl)pyrrolidin-2-one;(R)-1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)pyrrolidin-2-one;(R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(4-chlorophenyl)pyrrolidin-2-one;(3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-(methylsulfonyl)ethyl)pyrrolidin-2-one;(3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-(methylsulfonyl)ethyl)pyrrolidin-2-one;(S)-methyl5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-carboxylate;(S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine;(R)-5-(3-(cyanomethoxy)phenyl)-1-(4-chlorophenyl)pyrrolidin-2-one;(S)-methyl5-(4-chlorophenyl)-4-(3-hydroxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-carboxylate;(S)-3-(2-(4-chlorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-yl)phenol;(S)-2-(4-chlorophenyl)-1,1-dioxo-5-(pyrazin-2-yl)-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine;(S)-2-(4-chlorophenyl)-1,1-dioxo-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine;(S)—N,N-bis(4-methoxybenzyl)-3-(5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)propanesulfamide;(S)-2-(4-chlorophenyl)-1,1-dioxo-5-(3-(methylsulfonyl)propyl)-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine;(3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(3-(methylsulfonyl)propyl)pyrrolidin-2-one;(S)-2-(5-(4-chlorophenyl)-4-(3-(cyanomethoxy)phenyl)-1,1,-dioxo-1,2,5-thiadiazolidin-2-yl)acetonitrile;(S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-(pyrazin-2-yl)-1,2,5-thiadiazolidine;(S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-(pyridazin-3-yl)-1,2,5-thiadiazolidine;(S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-phenyl-1,2,5-thiadiazolidine;(S)-2-(5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)acetonitrile;(S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-((3,5-dimethylisoxazol-4-yl)methyl)-1,2,5-thiadiazolidine;(S)-methyl3-((5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)methyl)isoxazole-5-carboxylate;(S)-3-((5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)methyl)-1,2,4-oxadiazole;(S)-3-(2-(4-chlorophenyl)-1,1-dioxo-5-phenyl-1,2,5-thiadiazolidin-3-yl)phenol;(S)-3-(5-(4-chlorophenyl)-1,1-dioxo-4-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidin-2-yl)propane-1-sulfonamide;(S)-2-(4-chlorophenyl)-1,1-dioxo-5-phenyl-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine;(S)-4-((5-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidin-2-yl)methyl)-3,5-dimethylisoxazole;(S)-2-(4-chlorophenyl)-5-(4-fluorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine;(R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-(cyanomethoxy)phenyl)pyrrolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)oxazolidin-2-one;(S)-methyl5-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-dioxide-2-carboxylate;(S)-2-(4-(4-chlorophenoxy)phenyl)-3-(3-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-dioxide;(S)-4-(3-(m-tolyloxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-4-(3-(3-cyanophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-4-(3-(2-chlorophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-4-(3-(4-methoxyphenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-4-(3-(2-cyanophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-4-(3-(4-cyanophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(pyridin-2-yloxy)phenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(pyrimidin-2-yloxy)phenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-ethoxyphenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(cyclopropylmethoxy)phenyl)oxazolidin-2-one;(S)-4-(3-(3-(dimethylamino)propoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-4-(3-(cyanomethoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-4-(3-(2-hydroxyethoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)oxazolidin-2-one;5-(3-(benzyloxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-4-(3-(benzyloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-4-(3-hydroxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-2-yloxy)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;4-(3-(2-cyanophenoxy)phenyl)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;5-(3-(benzyloxy)phenyl)-1-(4-chlorophenyl)imidazolidin-2-one;4-(3-(benzyloxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;4-(3-(2-cyanophenoxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrimidin-2-yloxy)phenyl)imidazolidin-2-one;3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-2-yloxy)phenyl)imidazolidin-2-one;3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-3-yloxy)phenyl)imidazolidin-2-one;3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-4-yloxy)phenyl)imidazolidin-2-one;3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one;4-(3-(4-methoxyphenoxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;4-(3-(5-aminopyrazin-2-yloxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrimidin-5-yloxy)phenyl)imidazolidin-2-one;(4S,5S)-1-((3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-N-(piperidin-1-yl)-1H-1,2,3-triazole-4-carboxamide;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(morpholinomethyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(morpholinomethyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one;(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-5-(morpholinomethyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-(ethylsulfonylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)oxazolidin-2-one;ethyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperidine-4-carboxylate;tert-butyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1,4-diazepane-1-carboxylate;(4S,5S)-3-(4-chlorophenyl)-5-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;ethyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate;(4S,5S)-3-(4-chlorophenyl)-5-((4-(ethylsulfonyl)piperazin-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-cyclopentyl-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-5-((4-acetyl-1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-isopentyl-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(2-methoxyphenyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((5-(2-(diethylamino)ethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(2-(piperidin-1-yl)ethyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-((diethylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-(morpholinomethyl)-4-(3-(pyrazin-2-yloxy)phenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-((isopropylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(ethylsulfonyl)piperazin-1-yl)methyl)oxazolidin-2-one; ethyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;(4S,5S)-3-(4-chlorophenyl)-5-((4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-5-((4-acetyl-1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-5-((4-(azepan-1-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-((4-methylpiperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;tert-butyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)pyrrolidin-3-ylcarbamate;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-ethoxy-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((5-(6-chloropyridin-3-yl)-2H-tetrazol-2-yl)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-phenylpiperidin-1-yl)methyl)oxazolidin-2-one;(4S,5R)-3-(4-chlorophenyl)-5-((5-chloropyridin-2-yloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(pyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;ethyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-ethoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;ethyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyrimidin-2-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyrazin-2-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-methyl-2-oxopyridin-1(2H)-yl)methyl)oxazolidin-2-one;(4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-methylpyridin-2-yloxy)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(imidazo[1,2-a]pyridin-6-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((3-oxo-4-(pyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(3,5-dimethylphenyl)-3-oxopiperazin-1-yl)methyl)oxazolidin-2-one;(S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-1-(pyrazin-2-yl)imidazolidin-2-one;N-(3-(1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide;(4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((4-((3-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((4-((5-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;ethyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate;benzyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2-oxopiperidine-4-carboxylate;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;4-(1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)benzonitrile;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-((tetrahydrofuran-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((4-ethoxy-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;ethyl2-(2-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazol-5-yl)acetate;(4S,5S)-3-(4-chlorophenyl)-5-((5-(2-hydroxyethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(2-morpholinoethyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((1-(tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((3-(tetrahydrofuran-3-yl)isoxazol-5-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;tert-butyl4-((4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate;ethyl2-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazole-5-carboxylate;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-phenyl-1H-imidazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-((tetrahydrofuran-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-((piperidin-1-yl)methyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;tert-butyl4-(2-(((4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazol-5-yl)piperidine-1-carboxylate;tert-butyl4-(1-(((4S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)-1H-tetrazol-5-yl)piperidine-1-carboxylate;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-phenyl-1H-imidazol-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)-4-(3-(trifluoromethoxy)phenyl)oxazolidin-2-one;ethyl4-(((4S,5S)-3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethoxy)phenyl)oxazolidin-5-yl)methyl)piperazine-1-carboxylate;(4S,5S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;6-(4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazin-1-yl)pyridine-3-carbonitrile;(4S,5S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one;(4S,5R)-5-((5-cyanopyridin-2-yloxy)methyl)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)oxazolidin-2-one;4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1-(6-methoxypyridin-3-yl)piperazin-2-one;(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(6-methoxypyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one;4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1-(6-methoxypyridin-2-yl)piperazin-2-one;tert-butyl4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-3-oxopiperazine-1-carboxylate;(4S,5S)-3-(4-chlorophenyl)-5-((4-(4-fluoropyridin-2-yl)piperazin-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one;ethyl3-((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)propanoate;(4S,5S)-3-(4-chlorophenyl)-5-((3-(diethylamino)pyrrolidin-1-yl)methyl)-4-(3-fluorophenyl)oxazolidin-2-one;tert-butyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)pyrrolidin-3-ylmethylcarbamate;(S)-3-(4-chlorophenyl)-1-((5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(pyridin-3-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(4-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethanesulfonamide;(S)-3-(4-chlorophenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-propylacetamide;(S)-3-(4-chlorophenyl)-1-(2-oxo-2-(piperidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(piperidin-1-yl)acetamide;(S)-tert-butyl4-(2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetyl)piperazine-1-carboxylate;(S)-3-(4-chlorophenyl)-1-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-((5-(4-chlorophenyl)oxazol-2-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-methyl3-((3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)isoxazole-5-carboxylate;(S)-3-(4-chlorophenyl)-1-(2-morpholinoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(4-hydroxypiperidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(3-morpholinopropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-1-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(piperidin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(morpholinosulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propane-1-sulfonamide;(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(2-hydroxyethyl)ethanesulfonamide;(S)-3-(4-chlorophenyl)-1-((6-morpholinopyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-((6-(piperidin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-1-((6-(bis(2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(4S)-3-(4-chlorophenyl)-1-(3-(3-(diethylamino)pyrrolidin-1-yl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-1-(2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)ethyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(morpholinosulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propane-1-sulfonamide;(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(2-hydroxyethyl)ethanesulfonamide;(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(2-hydroxyethyl)ethanesulfonamide;(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)imidazolidin-2-one;(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)imidazolidin-2-one;(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-2-oxoimidazolidin-1-yl)ethanesulfonamide;(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(2-hydroxyethoxy)phenyl)imidazolidin-2-one;(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-4-(3-(2-hydroxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)ethanesulfonamide;(S)—N-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylsulfonyl)acetamide;(S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;tert-butyl4-((2-((S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)ethyl)sulfonyl)piperazine-1-carboxylate;(S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-1-(2-((piperazin-1-yl)sulfonyl)ethyl)imidazolidin-2-one;(S)-1-(4-chlorophenyl)-5-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(pyridazin-3-yloxy)phenyl)oxazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(morpholinosulfonyl)ethyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(pyridazin-3-yloxy)phenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)imidazolidin-2-one;(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-1-yl)ethanesulfonamide;(S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(morpholinosulfonyl)ethyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)imidazolidin-2-one;(S)-2-(3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)ethanesulfonamide;(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-1-yl)ethanesulfonamide;(S)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-methoxyphenyl)imidazolidin-2-one;(S)-3-(5-(4-chlorophenoxy)pyrazin-2-yl)-4-(3-methoxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;(S)-1-(2-(azetidin-1-ylsulfonyl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-1-(2-(azetidin-1-ylsulfonyl)ethyl)-3-(4-chlorophenyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one;(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(4-(methylsulfonyl)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one;(S)-4-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)benzenesulfonamide;(S)-4-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-1-yl)benzenesulfonamide;(S)-methyl3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propanoate;(S)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propanamide;(S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)sulfamide;(S)-3-(4-chlorophenyl)-1-(pyrazin-2-yl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)methanesulfonamide;(S)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-2-yloxy)phenyl)imidazolidin-2-one;(4S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-1-(2-(1,3-dioxan-2-yl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(4-(4-chlorophenoxy)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;3-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)oxazolidin-2-one;1-(2-(1H-pyrazol-1-yl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;1-(2-(1H-imidazol-1-yl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one;(S)-1-(4-(4-chlorophenoxy)phenyl)-2-(nitromethylene)-5-(3-(trifluoromethyl)phenyl)imidazolidine;(S)—N-(1-(4-chlorophenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)methanesulfonamide;(S)-3-(4-chlorophenyl)-4-(3-(6-methylpyridin-3-yloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;(S)-1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-1-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)urea;(S)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-1-yl)ethanesulfonamide;(S)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(morpholinosulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-3-(4-chlorophenyl)-1-(2-(piperazin-1-ylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)—N-(1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-ylidene)methanesulfonamide;(S)—N-(1-(4-chlorophenyl)-5-(3-(2-hydroxyethoxy)phenyl)imidazolidin-2-ylidene)methanesulfonamide;(S)—N-(1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-ylidene)sulfamide;(S)—N-(1-(4-chlorophenyl)-5-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-ylidene)methanesulfonamide;(S)-1-(2-(1,3-dioxan-2-yl)ethyl)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-1-yl)propanamide;(S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-cyano-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide;(S)-1-(2-(1H-1,2,4-triazol-3-yl)ethyl)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one;(S)-3-(3-(3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-2-oxoimidazolidin-4-yl)phenoxy)pyrazine-2-carbonitrile;(S)-3-(4-chlorophenyl)-4-(3-(3-ethylpyrazin-2-yloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one;and(S)-4-(3-(5-aminopyrazin-2-yloxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one.

Another embodiment provides for a method of treating a disease mediatedby the Cannabinoid-1 receptor (for example, an eating disorderassociated with excessive food intake like obesity, bulimia nervosa, andcompulsive eating disorders) comprising administration of to a patientin need of such treatment of a therapeutically effective amount of acompound selected from the Summary of the Invention (supra).

Another embodiment provides for a method of preventing obesity in aperson at risk for obesity comprising administration to said person ofabout 0.001 mg to about 100 mg per kg of a compound selected from theSummary of the Invention (supra).

Further compounds of the invention are detailed in the Examples andTable I, infra.

Pharmacology and Utility

Compounds of the invention inhibit the activity of CB1 and, as such, areuseful for treating diseases or disorders in which the activity of CB1contributes to the pathology and/or symptomology of the disease. Thisinvention further provides compounds of this invention for use in thepreparation of medicaments for the treatment of diseases or disorders inwhich CB1 activity contributes to the pathology and/or symptomology ofthe disease. CB1 mediated diseases or conditions include, but are notlimited to, metabolic disorders as well as conditions associated withmetabolic disorders including obesity, bulimia nervosa, compulsiveeating disorders, diabetes, arteriosclerosis, hypertension, polycysticovary disease, osteoporosis, cardiovascular disease, osteoarthritis,dermatological disorders, hypertension, insulin resistance,hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleepdisorders, and hyperlipidemic conditions; or psychiatric disorders suchas substance abuse, psychosis, depression, anxiety, stress, epilepsy,mania and schizophrenia; or cognitive disorders such as dementiaincluding Alzheimer's disease, memory deficits, short term memory lossand attention deficit disorders; or neurodegenerative disorders such asParkinson's Disease, cerebral apoplexy and craniocerebral trauma,hypotension, catabolism in connection with pulmonary dysfunction andventilator dependency; or cardiac dysfunction including valvulardisease, myocardial infarction, cardiac hypertrophy and congestive heartfailure); or the overall pulmonary dysfunction, transplant rejection,rheumatoid arthritis, migraine, neuropathy, multiple sclerosis,Guillain-Barre syndrome, the inflammatory sequelae of viralencephalitis, cerebral vascular accidents, inflammatory bowel disease,lupus, graft vs. host disease, T-cell mediated hypersensitivity disease,psoriasis, asthma, Hashimoto's thyroiditis, Guillain-Barre syndrome,cancer, contact dermatitis, allergic rhinitis, ischemic or reperfusioninjury, head trauma and movement disorders. The compounds are alsouseful for the treatment of substance abuse disorders, particularly toopiates, alcohol, marijuana, and nicotine including smoking cessation.The compounds are also useful for the treatment of eating disorders byinhibiting excessive food intake and the resulting obesity andcomplications associated therewith, including left ventricularhypertrophy. The compounds are also useful for the treatment ofconstipation and chronic intestinal pseudo-obstruction, as well as forthe treatment of asthma, osteopororsis, and cirrhosis of the liver.

Marijuana and its derivatives have been used for centuries for medicinaland recreational purposes. A major active ingredient in marijuana andhashish has been determined to be Δ9-Tetrahydrocannabinol (Δ9-THC). Thebiological action of Δ9-THC and other members of the cannabinoid familyoccurs through two G-protein coupled receptors termed CB1 and CB2. TheCB1 receptor is primarily found in the central and peripheral nervoussystems and to a lesser extent in several peripheral organs.

The CB2 receptor is found primarily in lymphoid tissues and cells. Threeendogenous ligands for the cannabinoid receptors derived fromarachidonic acid have been identified (anandamide, 2-arachidonoylglycerol, and 2-arachidonyl glycerol ether). Each is an agonist withactivities similar to Δ9-THC, including sedation, hypothermia,intestinal immobility, antinociception, analgesia, catalepsy,anti-emesis, and appetite stimulation.

The genes for the respective cannabinoid receptors have each beendisrupted in mice. The CB1 receptor knockout mice appeared normal andfertile. They were resistant to the effects of Δ9-THC and demonstrated astrong reduction in the reinforcing properties of morphine and theseverity of withdrawal syndrome. They also demonstrated reduced motoractivity and hypoalgesia. The CB2 receptor knockout mice were alsohealthy and fertile. They were not resistant to the central nervoussystem mediated effects of administered Δ9-THC. There were some effectson immune cell activation, reinforcing the role for the CB2 receptor inimmune system functions.

Excessive exposure to Δ9-THC can lead to overeating, psychosis,hypothermia, memory loss, and sedation.

Treatment of asthma with CB1 receptor modulators (such as CB1 inverseagonists) is supported by the finding that presynaptic cannabinoid CB1receptors mediate the inhibition of noradrenalin release.

Treatment of cirrhosis of the liver with CB1 receptor modulators issupported by the finding that a CB1 receptor modulator will reverse thelow blood pressure observed in rats with carbon tetrachloride-inducedliver cirrhosis and will lower the elevated mesenteric blood flow andportal vein pressure.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount (See, “Administration and Pharmaceutical Compositions”, infra) ofa compound of Formula I or a pharmaceutically acceptable salt thereof.For any of the above uses, the required dosage will vary depending onthe mode of administration, the particular condition to be treated andthe effect desired.

Administration and Pharmaceutical Compositions

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrollidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions can be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they can also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present invention witha carrier. A carrier can include absorbable pharmacologically acceptablesolvents to assist passage through the skin of the host. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin. Matrixtransdermal formulations can also be used. Suitable formulations fortopical application, e.g., to the skin and eyes, are preferably aqueoussolutions, ointments, creams or gels well-known in the art. Such cancontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

Compounds of the invention can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other substances used in the treatment of diseases ordisorders, such as, psychosis, memory deficit, cognitive disorders,migraine, neuropathy, neuroinflammatory disorders, cerebral vascularaccidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson'sdisease, schizophrenia, substance abuse disorders such as smokingcessation, osteoporosis, constipation, chronic intestinalpseudo-obstruction, cirrhosis of the liver, asthma, obesity, and othereating disorders associated with excessive food intake, obesity, etc.(see “Pharmacology and Utility”, supra). Where the compounds of theinvention are administered in conjunction with other therapies, dosagesof the co-administered compounds will of course vary depending on thetype of co-drug employed, on the specific drug employed, on thecondition being treated and so forth.

A combined preparation or pharmaceutical composition can comprise acompound of the invention as defined above or a pharmaceuticalacceptable salt thereof and at least one active ingredient selectedfrom:

a) anti-diabetic agents such as insulin, insulin derivatives andmimetics; insulin secretagogues such as the sulfonylureas, e.g.,Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptorligands such as meglitinides, e.g., nateglinide and repaglinide; insulinsensitizer such as protein tyrosine phosphatase-1B (PTP-1B) inhibitorssuch as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such asSB-517955, SB-4195052, SB-216763, N,N-57-05441 and N,N-57-05445; RXRligands such as GW-0791 and AGN-194204; sodium-dependent glucoseco-transporter inhibitors such as T-1095; glycogen phosphorylase Ainhibitors such as BAY R3401; biguanides such as metformin;alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon likepeptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; DPPIV(dipeptidyl peptidase IV) inhibitors such as DPP728, LAF237(vildagliptin—Example 1 of WO 00/34241), MK-0431, saxagliptin, GSK23A;an AGE breaker; a thiazolidone derivative (glitazone) such aspioglitazone, rosiglitazone, or(R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylicacid described in the patent application WO 03/043985, as compound 19 ofExample 4, a non-glitazone type PPAR gamma agonist e.g. GI-262570;Diacylglycerol acetyltransferase (DGAT) inhibitors such as thosedisclosed in WO 2005044250, WO 2005013907, WO 2004094618 and WO2004047755;

b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A(HMG-CoA) reductase inhibitors, e.g., lovastatin and related compoundssuch as those disclosed in U.S. Pat. No. 4,231,938, pitavastatin,simvastatin and related compounds such as those disclosed in U.S. Pat.Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such asthose disclosed in U.S. Pat. No. 4,346,227, cerivastatin, mevastatin andrelated compounds such as those disclosed in U.S. Pat. No. 3,983,140,velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin andrelated statin compounds disclosed in U.S. Pat. No. 5,753,675,rivastatin, pyrazole analogs of mevalonolactone derivatives as disclosedin U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393,2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No. 0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. Inaddition, phosphinic acid compounds useful in inhibiting HMG CoAreductase suitable for use herein are disclosed in GB 2205837; squalenesynthase inhibitors; FXR (farnesoid X receptor) and LXR (liver Xreceptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;

c) an anti-obesity agent or appetite regulating agent such asmelanocortin receptor (MC4R) agonists, melanin-concentrating hormonereceptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR)antagonists, galanin receptor modulators, orexin antagonists, CCKagonists, GLP-1 agonists, and other Pre-proglucagon-derived peptides;NPY1 or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropinreleasing factor agonists, histamine receptor-3 (H3) modulators, aP2inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoAcarboxylase (ACC) inihibitors, 11-β-HSD-1 inhibitors, adinopectinreceptor modulators; beta 3 adrenergic agonists, such as AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator,such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CalSF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-1 inhibitoras disclosed in WO2005011655, a lipase inhibitor, such as orlistat orATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT-933(Biovitrum)), monoamine reuptake inhibitors or releasing agents, such asfenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine,sertraline, chlorphentermine, cloforex, clortermine, picilorex,sibutramine, dexamphetamine, phentermine, phenylpropanolamine ormazindol, anorectic agents such as topiramate (Johnson & Johnson), CNTF(ciliary neurotrophic factor)/Axokine® (Regeneron), BDNF (brain-derivedneurotrophic factor), leptin and leptin receptor modulators,phentermine, leptin, bromocriptine, dexamphetamine, amphetamine,fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine,mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine,bupropion, topiramate, diethylpropion, benzphetamine,phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine;

d) anti-hypertensive agents such as loop diuretics such as ethacrynicacid, furosemide and torsemide; diuretics such as thiazide derivatives,chlorithiazide, hydrochlorothiazide, amiloride; angiotensin convertingenzyme (ACE) inhibitors such as benazepril, captopril, enalapril,fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril andtrandolapril; inhibitors of the Na-K-ATPase membrane pump such asdigoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan,terteo-thiorphan, SQ29072; ECE inhibitors e.g. SLV306; ACE/NEPinhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensinII antagonists such as candesartan, eprosartan, irbesartan, losartan,telmisartan and valsartan, in particular valsartan; renin inhibitorssuch as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168;beta-adrenergic receptor blockers such as acebutolol, atenolol,betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol andtimolol; inotropic agents such as digoxin, dobutamine and milrinone;calcium channel blockers such as amlodipine, bepridil, diltiazem,felodipine, nicardipine, nimodipine, nifedipine, nisoldipine andverapamil; aldosterone receptor antagonists; aldosterone synthaseinhibitors; and dual ET/AII antagonist such as those disclosed in WO00/01389.

e) a HDL increasing compound;

f) Cholesterol absorption modulator such as Zetia® and KT6-971;

g) Apo-A1 analogues and mimetics;

h) thrombin inhibitors such as Ximelagatran;

i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone;

j) Inhibitors of platelet aggregation such as aspirin, clopidogrelbisulfate;

k) estrogen, testosterone, a selective estrogen receptor modulator, aselective androgen receptor modulator;

l) a chemotherapeutic agent such as aromatase inhibitors e.g. femara,anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors,microtubule active agents, alkylating agents, antineoplasticantimetabolites, platin compounds, compounds decreasing the proteinkinase activity such as a PDGF receptor tyrosine kinase inhibitorpreferably Imatinib({N-{5-[4-(4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine})described in the European patent application EP-A-0 564 409 as example21 or4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidedescribed in the patent application WO 04/005281 as example 92; and

m) an agent interacting with a 5-HT₃ receptor and/or an agentinteracting with 5-HT₄ receptor such as tegaserod described in the U.S.Pat. No. 5,510,353 as example 13, tegaserod hydrogen maleate, cisapride,cilansetron;

n) an agent for treating tobacco abuse, e.g., nicotine receptor partialagonists, bupropion hypochloride (also known under the tradename Zyban®)and nicotine replacement therapies;

o) an agent for treating erectile dysfunction, e.g., dopaminergicagents, such as apomorphine), ADD/ADHD agents (e.g., Ritalin®,Strattera®, Concerta® and Adderall®);

p) an agent for treating alcoholism, such as opioid antagonists (e.g.,naltrexone (also known under the tradename ReVia®) and nalmefene),disulfuram (also known under the tradename Antabuse®), and acamprosate(also known under the tradename Campral®)). In addition, agents forreducing alcohol withdrawal symptoms may also be co-administered, suchas benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin,and gabapentin (Neurontin®);

q) other agents that are useful including anti-inflammatory agents(e.g., COX-2 inhibitors); antidepressants (e.g., fluoxetinehydrochloride (Prozac®)); cognitive improvement agents (e.g., donepezilhydrochloride (Aircept®) and other acetylcholinesterase inhibitors);neuroprotective agents (e.g., memantine); antipsychotic medications(e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine(Zyprexa®));

or, in each case a pharmaceutically acceptable salt thereof; andoptionally a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

Processes for Making Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1991.

In the following schemes, several methods of preparing the compounds ofthe present invention are illustrative. One of skill in the art willappreciate that these methods are representative, and in no wayinclusive of all methods for preparing the compounds of the presentinvention. The radicals in the schemes are as described in the Summaryof the Invention (supra). In each of the reaction schemes below, R₁ is4-chloro-phenyl.

An illustration of the synthesis of the compounds in the presentinvention of Formula I is given in the following reaction schemes

An illustration of the synthesis of the compounds in the presentinvention of formula I, in which Z₂=CH₂ and Z₁=O, is given in Scheme 1.Succinic anhydride (I-a, n=1) or glutaric anhydride (I-b, n=2) can beconverted into I-c by refluxing with the designated aniline in toluenefollowed by cyclization that is mediated by thionyl chloride. Reductionof I-c with DIBAL in CH₂Cl₂ under low temperature (preferably at −78°C.) give I-d, which then undergoes Friedel-Crafts reaction with anappropriate arene under acidic condition to provide I-e.

An illustration of the synthesis of the compounds in the presentinvention of formula I, in which Z₂=O and Z₁=O, is given in Scheme 2.Oxazolidinone II-b can be synthesized by Sharpless asymmetricaminohydroxylation of alkene II-a followed by cyclization under basicconditions (N. Barta et al. Org. Lett. 2000, 2, 2821). 3-aryloxazolidinones II-c can then be obtained by copper catalyzed N-arylationof II-b. For procedures of Sharpless asymmetric aminohydroxylation, seeSharpless, K. B. et al. (1996). “N-Halocarbamate salts lead to moreefficient catalytic asymmetric aminohydroxylation.” Angew. Chem. Int.Ed. Engl. 35(23/24): 2813-2816; Sharpless, K. B. et al. (1998). “Fromstyrenes to enantiopure α-arylglycines in two steps.” J. Am. Chem. Soc.120: 1207-17. For copper mediated N-arylation reactions, see: Buchwald,S. L. et al. (2001). “A general and efficient copper catalyst for theamidation of aryl halides and the N-arylation of nitrogen heterocycles.”J. Am. Chem. Soc. 123(31): 7727-9.

An illustration of the asymmetric synthesis of1,5-diaryl-imidazolidin-2-one is given in Scheme 3. The hydroxycarbamateIII-b can be obtained by a standard Sharpless aminohydroxylationprocess. Tosylation of the alcohol followed by a nucleophilicsubstitution with sodium azide provides azide III-d which can then beconverted into III-e by a sequence of hydrogenolysis, reductiveamination with p-methoxy benzaldehyde followed by in situ cyclization.The resulting imidazolidin-2-one III-e is then subjected to a coppercatalyzed N-arylation to provide imidazolidin-2-one III-f, which is thenfollowed by acidic deprotection of the p-methoxybenzyl group to yieldIII-g.

An alternative asymmetric synthesis of 1,5-diaryl-imidazolidin-2-one isgiven in Scheme 4. Styrene IV-a is converted into aminoalcohol IV-c viaa standard Sharpless asymmetric aminohydroxylation (AA) reactionfollowed by hydrogenolysis to remove the Cbz protection group.Bis-tosylation of IV-c followed by in situ cyclization provides tosylactivated aziridine IV-d, which undergoes a LiClO₄-catalyzedconfiguration-inverted ring opening reaction with aniline Ar₁NH₂ toprovide intermediate IV-e (Yadav, J. S.; Reddy, B. V. S.; Jyothirmai,B.; Murty, M. S. R. Synlett 2002, 53). IV-e readily cyclizes withtriphosgene to provide compound IV-f. Magnesium reductive cleavage ofthe N-Ts group in IV-f finishes the desired1,5-diaryl-imidazolidin-2-one IV-g.

The synthesis of racemic form of IV-g uses the same route with somesimplifications, in which the racemic aziridine can be obtained directlyfrom styrene IV-a via an iodine-catalyzed aziridination reaction usingChloramine-T as a nitrogen source (Ando, T.; Kano, D.; Minakata, S.;Ryu, I.; Komatsu, M. Tedrahedron 1998, 54, 13485). For other conditionsused for aziridination reactions, see J. U. Jeong, B. Tao, I. Sagasser,H. Henniges and K. B. Sharpless, Bromine-Catalyzed Aziridination ofOlefins. A Rare Example of Atom-Transfer Redox Catalysis by a Main GroupElement, J. Am. Chem. Soc., 120, 6844 (1998); A. V. Gontcharov, H. Liuand K. B. Sharpless, tert-Butylsulfonamide. A New Nitrogen Source forCatalytic Aminohydroxylation and Aziridination of Olefins, Org. Lett.,1, 783 (1999) and references cited therein.

An illustration of the asymmetric synthesis of 5-substituted-4-aryloxazolidinones is depicted in Scheme 5. Compound V-b is prepared viastandard Sharpless aminohydroxylation process (K. L. Reddy and K. B.Sharpless, J. Am. Chem. Soc. 1998, 120, 1207). The intermediatecarbamate is then deprotected under standard acidic conditions, which isthen followed by conversion into oxazolidinone V-c with carbonyldiimidazole, or a suitable equivalent. Copper-catalyzed N-arylationyields V-d. The carboxylate ester is then reduced with sodium borohyrideto give alcohol V-e, which can then be converted in to V-f vianucleophilic replacement of a corresponding mesylate with a suitablenucleophile (e.g. amines, thiol and etc.).

An alternative synthesis of 5-substituted-4-aryl oxazolidinones is shownin Scheme 6. Oxazolidinone-5-carboxylic ester VI-a is treated withsodium borohydride to give the intermediate alcohol which is thenconverted into tetrahydropyranyl (THP) ether VI-b. Copper catalyzedN-arylation gives VI-c, which is then subjected to acidic deprotectionof the THP group, followed mesylation and nucleophilic displacement (forexample, with a amine R₂NH) to give the 5-substituted analogues VI-d.

An illustration of the asymmetric synthesis of morpholinones is depictedin Scheme 7. Asymmetric aminohydroxlation of styrene VII-a is followedby conversion into ether VII-c. Deprotection of the t-butoxycarbamategroup is followed by base-mediated cyclization to give morpholinoneVII-d. Copper mediated N-arylation gives the morpholinone VII-e.

An illustration of the conversion of oxazolidinone VIII-a into thecorresponding 1,2,3-triazole derivatives VIII-c is depicted in Scheme 8.The alcohol VIII-a is first converted into the requisite mesylate, whichis then treated with sodium azide to give azide VIII-b. The azide isthen subjected to copper mediated cycloaddition with an alkyne RCCH togive triazole VIII-c. For an efficient synthesis of 1,2,3-triazoles fromazide and alkyne, see: P. Wu, A. K. Feldman, A. K. Nugent, C. J. Hawker,A. Scheel, B. Voit, J. Pyun, J. M. J. Fréchet, K. B. Sharpless and V. V.Fokin, Efficiency and Fidelity in a Click Chemistry Route to TriazoleDendrimers via the Cu(I)-Catalyzed Ligation of Azides and Alkynes,Angew. Chem. Int. Ed., 43, 3928 (2004). For an efficient synthesis oftetrazoles from azide and nitrile, see: Z. P. Demko and K. B. Sharpless,An Intramolecular [2+3] Cycloaddition Route to Fused 5-HeterosubstitutedTetrazoles, Org. Lett., 3, 4091 (2001); Z. P. Demko and K. B. Sharpless,Preparation of 5-Substituted-1H-Tetrazoles from Nitriles in Water, J.Org. Chem., 66, 7945 (2001). For reviews on click chemistry in drugdiscovery, see: H. C. Kolb and K. B. Sharpless, The Growing Impact ofClick Chemistry on Drug Discovery, Drug Discovery Today, 8, 1128 (2003);H. C. Kolb, M. G. Finn and K. B. Sharpless, Click Chemistry: DiverseChemical Function From a Few Good Reactions, Angew. Chem., 40, 2004(2001).

An alternative racemic synthesis of 1,5-diaryl-imidazolidin-2-one isdescribed in Scheme 9. Styrene IX-a is converted into aziridine IX-b viaan iodine-catalyzed aziridination reaction using Chloramine-T as anitrogen source (Ando, T.; Kano, D.; Minakata, S.; Ryu, I.; Komatsu, M.Tedrahedron 1998, 54, 13485). Aziridine IX-b undergoes a regioselectivecycloaddition reaction with aryl isocyanate OCN—Ar₂ to form compoundIX-c (Nadir, U. K.; Basu, N. Tedrahedron Lett. 1992, 33, 7949).Magnesium reductive cleavage of the Ts group furnishes the desired1,5-diaryl-imidazolidin-2-one IX-d.

An illustration of the synthesis of 1,5-diaryl-imidazolidine-2,4-dioneis given in Scheme 10. N-Aryl amino acid X-b is synthesized from α-aminoacid X-a and aryl halide under the CuI-catalyzed coupling reactioncondition described in Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J.Am. Chem. Soc. 1998, 120, 12459. Compound X-b is cyclized with potassiumcyanate in acidic media to finish 1,5-diaryl-imidazolidine-2,4-dioneX-c.

An illustration of the asymmetric synthesis of 5-aryl substitutedpyrrolidin-2-one exemplified by structure XI-h is depicted in Scheme 11.N-Boc-protected α-arylglycines XI-c is be easily prepared via thestandard Sharpless two-step process from styrenes XI-a (K. L. Reddy andK. B. Sharpless, J. Am. Chem. Soc. 1998, 120, 1207). The monoalkylatedMeldrum's acid XI-e is obtained from XI-c by condensed with Meldrum'sacid, followed by complete reduction of its keto functionality (M.Smrcina, P. Majer, E. Majerova, T. A. Guerassina and M. A. Eissenstat,Tetrahedron Lett. 1997, 53, 12867; B. Hin, P. Majer and T. Tsukamoto, J.Org. Chem. 2002, 67, 7365). XI-e undergoes thermal ring closure to aN-Boc-protected 3-carboxy pyrrolidin-2-one XI-f, which can be furthertransformed into 5-aryl substituted pyrrolidin-2-one XI-g upon treatmentwith TFA. Buchwald copper-catalyzed N-arylation yields XI-h in goodyields.

An alternative asymmetric synthesis of 5-aryl substitutedpyrrolidin-2-one exemplified by structure XII-g is depicted in scheme12. γ-Ketoester XII-c can be prepared using a Rh-catalyzed chelationassisted hydroacylation of aromatic aldehyde XII-a with methyl acrylateXII-b (Eun-Ae Jo and Chul-Ho Jun, Eur. J. Org. Chem. 2006, 2504-2507).Asymmetric reduction of XII-c using (−)-B-chlorodiisopinocamphenylborane((−)-DIP-Chloride) affords hydroxyl ester XII-d, which is then convertedinto the corresponding lactone XII-e (P. V. Ramachandran, S. Pitre, andH. C. Brown, J. Org. Chem. 2002, 67, 5315-5319.). A Weinreb amidationand Mitsunobu cyclodehydration yields the 5-aryl substitutedpyrrolidin-2-one in good yield and enantiomeric purity (I. M. Bell, D.C. Beshore, S, N. Gallicchio, and T. M. Williams, Tetrahedron Lett.2000, 41, 1141-1145).

Several new synthetic methods have recently been introduced that havemade the copper catalyzed cross-coupling of most nitrogen containingfunctional groups to sp²-halides more accessible. (Ley et al. Angew.Chem. Int. Ed. 2003, 42, 5400). The majority of these new methods employa variety of multidentate copper chelators that make the construction ofsp²-carbon-heteroatom bonds more facile. (Buchwald et al. J. Org. Chem.2004, 59, 5578 and references cited therein). Despite these advances,relatively high heat (≧100° C.) and long reaction times (≧24 h) arestill mandatory to obtain good results. Therefore, methods with improvedreactivity, broader reaction scope, and substrate tolerance are still indemand Since many groups have exploited the donor ligand effects toimprove the cross-coupling, attention has shifted away from the othervital components in the reaction. A non-obvious replacement of theconventional bases (K₂CO₃, K₃PO₄, Cs₂CO₃) with the milder cesiumfluoride catalyzes the coupling of a number of amides, carbamates, andnitrogen heterocycles to aryl iodides, in many cases at roomtemperature. Furthermore, substrates that were incompatible with thecopper catalyzed reaction employing the stronger bases may be compatiblewith CsF.

Optimized conditions for substrates that were incompatible with theconventional conditions (CuI, diamine, K₃PO₄ or K₂CO₃, 100-110° C.) weredetermined with simpler substrates. Weaker bases, such as KHCO₃, KOAc,or CsF, would avoid unwanted side reactions. Screening of these basesrevealed efficient coupling of oxazolidinone 1 with aryl iodide 2 togive the product 3 in good yield at 100° C. (Scheme 1). Cesium fluoriderequired only 2 h, whereas KHCO₃ and KOAc required 18 h. When the samereactants were treated with CsF at 25° C. for 18 h, a nearlyquantitative yield of 3 was obtained. Further experiments revealed thatTHF, ACN, or EtOAc (Table 2) were optimal solvents for this reaction andthat a minimum of 2-2.5 equivalents of CsF were required. Since CsFshowed an improved ability to promote the CuI-catalyzed reaction in thismodel system, its ability to promote the coupling of other substrateswas investigated.

Base % Yield KHCO₃ 89 (18 h) KOAc 80 (18 h) CsF 81 (2 h) CsF 99 (18 h,RT)

A number of control reactions were performed to show that the effectcannot simply be attributed to the presence of cesium or to fluoride,but to a synergy between CsF and CuI. When CsF is replaced by KF, K₂CO₃,or Cs₂CO₃ the yield was significantly lower at 25° C. (Table 3, Entries5-7) and at 100° C. (Table 3, Entry 5). These reduced yields could beattributed to the reduced solubility of these salts at room temperaturein ethyl acetate compared to the solubility of CsF. However, when KF andK₂CO₃ are combined with a substoichiometric quantity of CsF, a 3.5 to10-fold increase in yield was observed (Table 3, Entries 8, 9). Theseresults suggest that some synergic effect exist between CsF and CuI toaccount for the dramatic increase in yield.

TABLE 2 Solvent Screen for N-Arylation Reaction using CsF as Base^(a)

Entry Solvent 100° C.^(b) 60° C.^(b) 25° C.^(b) 1 EtOAc 99 99 99 2 THF98 99 92 3 ACN 99 94 90 4 DMSO 94 — — 5 DME 84 — — 6 DMF 81 — 55 7Dioxane 73 — — 8 Toluene 59 — —

TABLE 3 CsF Condition Screening for the N-Arylation Reaction^(a)

Entry Conditions Yield Entry Conditions Yield 1 2 eq. CsF 99  6 2 eq.K₂CO₃ 12 2 1.5 eq. CsF 55  7 2 eq. Cs₂CO₃ trace^(d) 3 1.2 eq. CsF 43  82 eq. K₂CO₃ + 43 0.2 eq. CsF 4 1.0 eq. CsF 23  9 2 eq. KF + 0.2 40 eq.CsF 5 2 eq. KF 4; 21^(c) 10 2 eq. CsBr  9 ^(a)Conditions: 1.1equivalents 1, 1.0 equivalents 2, 2 mL EtOAc; ^(b)% isolated yield;^(c)100° C., 16 h; ^(d)as detected by LC-MS.

The reactions of several amides relevant to the claimed compounds withvarious aryl iodides is detailed in Table 4. These reactions wereperformed at 1 mmol scale with 2.5 equivalents of CsF, 5 mol % CuI, and10 mmol % N,N′-dimethylethylenediamine in either THF or EtOAc typicallyfor 18-24 h. We found that most amides and carbamates coupled veryefficiently to aryl iodides with p- or m-substituents at 25° C., withonly 4u requiring heating to 60° C. (Table 4). The efficiency of theseconditions on 10 mmol scale was demonstrated at 60° C. with example 4b,proving that these conditions may be scalable. Electron-poor andelectron-rich aryl halides coupled with near equal efficiency underthese conditions. Overall, excellent substrate tolerance and selectivitywere observed. Example 4i is noteworthy as no halide exchange wasobserved with these conditions. The slightly reduced yield for 4n couldbe explained by the steric hindrance imposed by the methyl group, or toperhaps the slightly higher expected pKa for the starting amide comparedto its des-methyl congener. The proximal ester group in example 4oprobably aided the formation of the Cu-coordinated intermediate, leadingto a nearly quantitative yield. Furthermore, no racemization orhydrolysis was observed with these conditions, but was a problem withthe conventional bases. Aryl halides with o-substituents are known tosuppress the N-arylation of most substrates; this limitation wasovercome by coupling those substrates at 85-100° C. (Table 4, 4f-g).

TABLE 4 Substrate Scope with Iodides

4a-y

^(a)Yields refer to isolated yields. ^(b)83% at 25° C. ^(c)60° C. ^(d)inEtOAc. ^(e)10 mmol scale. ^(f)in ACN at 85° C. ^(g)in ACN at 100° C.^(h)86% ee

The amidation of aryl bromides is summarized in Table 5. Aryl andheteroaryl bromides usually require higher reaction temperatures and/orlonger reaction times than the corresponding aryl iodides. Even though anumber of new ligands have been introduced by several groups to reducethese barriers, none have so far completely succeeded. When arylbromides were subjected to our CsF promoted conditions, we obtained goodto excellent results in most cases when the substrates were treated 100°C. (Table 5).

TABLE 5 Substrate Scope with Aryl Bromides

5a-5f

^(a)Yields refer to isolated yields. ^(b)DMA 110° C.

In summary, the advantages of CsF mediated coupling are as follows:

a. Cesium fluoride (CsF) promoted N-arylation reactions proceed well atroom temperature with a variety of substrates whereas, for other bases,elevated temperatures are required.

b. CsF is compatible with most N-arylation reaction conditions in theart, yet CsF promotes the coupling at lower temperatures and shorterreaction times than the reported conditions.

c. The weaker basicity of CsF offers greater versatility in promotingthe C—N coupling reaction of base sensitive substrates; and d. Theconvenience of the milder reaction conditions proves to be more usefulin combinatorial or parallel reaction formats and in large scalesyntheses.

Consequently, an embodiment of the present invention provides for aprocess of preparing a compound of the Summary of the Invention with agreater than 80% yield. Said compound contains an aryl bonded directlyto a group selected from an amide, a carbamate and a nitrogen containingheterocycle forming a compound of Formula I. The process comprises:reacting an aryl-halide with an amide, a carbamate or a nitrogencontaining heterocycle in the presence of a copper catalyst; cesiumfluoride; and a solvent. The reaction is carried out at a temperature ofless than or equal to 100° C. and requires less than or equal to 24hours for completion.

In a further embodiment, the copper catalyst is copper iodide.

In a further embodiment, the solvent is selected from THF, CAN, DMSO,DME, DMF, Dioxane, toluene and EtOAc.

In a further embodiment, the reaction is carried out at a temperature ofless than or equal to 75° C.

In a further embodiment, the reaction is carried out at a temperature ofless than or equal to 50° C.

In a further embodiment, the reaction is carried out at a temperature ofless than or equal to 25° C.

In a further embodiment, the reaction takes between 18 and 24 hours forcompletion.

Detailed descriptions of the synthesis of compounds of the Invention aregiven in the Examples, infra.

Additional Processes for Making Compounds of the Invention

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventioncan be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, or the like) in a suitable inert organic solvent(e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

(a) that of reaction scheme 1-12; and

(b) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(c) optionally converting a salt form of a compound of the invention toa non-salt form;

(d) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(e) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(f) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;

(g) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(h) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The present invention is further exemplified, but not limited, by thefollowing Examples that illustrate the preparation of compounds of theinvention.

Example 2 and Example 55-(4-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-oneand5-(2-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one

Step A: A mixture of succinic anhydride (250 mg, 2.50 mmol) and4-amino-4′-chloro diphenylether (500 mg, 2.27 mml) in toluene is heatedto 110° C. for 14 h. and cooled down to room temperature. SOCl₂ (1.5 mL)is added into the mixture and stirred at room temperature for 8 h. Afterthe solvent is removed under vacuum, the residue is treated withsaturated NaHCO₃ aqueous solution (20 mL) and extracted with CHCl₃ (3×50mL). The combined organic layer is washed with brine and dried (MgSO₄).After filtering the drying agent, the filtrate is concentrated andpurified by flash column chromatography (silica gel, EtOAc/hexane30%˜80%) to provide1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidine-2,5-dione as white solid(570 mg, 83%).

Step B: A solution of1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidine-2,5-dione (100 mg, 0.33mmol) in anhydrous CH₂Cl₂ (1.5 mL) is cooled down to −78° C. in a dryice bath. DIBAL-H (0.6 mL, 1 M solution in hexane, 0.66 mmol) is addedinto the solution dropwise under N₂. After the addition, the mixture isstirred at the same temperature for 10 min and quenched by H₂O (10 mL).The mixture is warmed up to room temperature and extracted with CH₂Cl₂(3×10 mL). The combined organic layer is washed with brine and dried(MgSO₄). After filtering the drying agent, the filtrate is concentratedand purified by flash column chromatography (silica gel, EtOAc) toprovide the(±)-1-[4-(4-chloro-phenoxy)-phenyl]-5-hydroxy-pyrrolidin-2-one as offwhite solid (72 mg, 72%).

Step C: To a mixture of1-[4-(4-chloro-phenoxy)-phenyl]-5-hydroxy-pyrrolidin-2-one (10 mg, 0.033mmol) and TFA (0.2 mL) in CH₂Cl₂ (0.8 mL) is added 3-trifluoroaniline(50 mL). After stirring at 40° C. for 14 h, the mixture is cooled andconcentrated. The resulted residue is treated with saturated NaHCO₃aqueous solution (1 mL) and extracted with EtOAc (3×3 mL). The combinedorganic layers is concentrated and purified by preparative LC/MS toprovide the title compound5-(4-amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-oneas major product (11 mg, 75%, example 2) and5-(2-amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-oneas minor product (2.52 mg, 17%, example 5). Example 2: ¹H NMR (CDCl₃,400 MHz) δ 7.27 (d, 2H), 7.23 (d, 1H), 7.17 (d, 2H), 7.14 (dd, 1H), 6.89(d, 2H), 6.88 (d, 2H), 6.71 (d, 1H), 6.02 (br, 2H), 5.14 (dd, 1H),2.64-3.0 (m, 3H), 2.05-2.13 (m, 1H); HPLC-MS calculated forC₂₃H₁₈ClF₃N₂O₂ (M+H⁺) 447.1, found 447.1. Example 5: ¹H NMR (CDCl₃, 400MHz) δ 7.40 (d, 3H), 7.25 (d, 2H), 7.15 (d, 2H), 7.14 (dd, 1H), 6.90 (d,2H), 6.88 (d, 2H), 6.76 (t, 1H), 5.25 (dd, 1H), 4.24 (br, 2H), 2.56-2.80(m, 3H), 2.05-2.18 (m, 1H); HPLC-MS calculated for C₂₃H₁₈ClF₃N₂O₂ (M+H⁺)447.1, found 447.1.

Example 31-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one

A solution of t-butyl nitrite (4.62 mg, 0.045 mmol) in DMF (0.2 mL) isheated to 65° C. while5-(4-amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one(10 mg, 0.022 mmol) in DMF (0.2 mL) is added in dropwise. The resultedmixture is stirred at 65° C. for an extra 5 min and then cooled down toroom temperature. The reaction mixture is treated with 2 N HCl (5 mL)and extracted with EtOAc (3×3 mL). The combined organic layers isconcentrated and purified by flash column chromatography (silica gel,EtOAc/hexane 0˜50%) to provide the title compound1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-pyrrolidin-2-oneas colorless oil (˜7 mg, 72%). ¹H NMR (CDCl₃, 400 MHz) δ 7.53 (d, 1H),7.47 (s, 1H), 7.46 (d, 1H), 7.41 (t, 1H), 7.31 (d, 2H), 7.25 (d, 2H),6.88 (d, 2H), 6.86 (d, 2H), 5.28 (t, 1H), 2.60-2.80 (m, 3H), 1.99-2.02(m, 1H); HPLC-MS calculated for C₂₃H₁₇ClF₃NO₂ (M+H⁺) 432.1, found 432.1.

Example 4(S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one

Step A: (S)-(3-Trifluoromethyl-phenyl)-oxazolidin-2-one can besynthesized from 3-trifluoromethylstyrene by using the method reportedby N. Barta et al. (Org. Lett. 2000, 2, 2821). HPLC-MS calculated forC₁₀H₈F₃NO₂ (M+H⁺) 232.1, found 232.1.

Step B: A mixture of 4(S)-(3-trifluoromethyl-phenyl)-oxazolidin-2-one(10 mg, 0.043 mmol), 4-chloro-4′-iodo-diphenyl ether (17.1 mg, 0.052mmol), K₃PO₄ (18 mg, 0.086 mmol), catalytic amount of CuI andtrans-1,2-cyclohexyldiamine in dioxane (0.5 mL) is degassed and heatedto 100° C. under N₂ for 2 h. After cooling down to room temperature, themixture is treated with saturated aqueous NH₄Cl solution (3 mL) andextracted with EtOAc (3×3 mL). The combined organic layers isconcentrated and purified by flash column chromatography (silica gel,EtOAc/hexane 0˜50%) to provide the titled compound(S)-3-[4-(4-chloro-phenoxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-oneas colorless oil (9 mg, 48%). ¹H NMR (CDCl₃, 400 MHz) δ 7.61 (t, 1H),7.55 (s, 1H), 7.52 (d, 2H), 7.30 (d, 2H), 7.25 (d, 2H), 6.90 (d, 2H),6.87 (d, 2H), 5.42 (dd, 1H), 4.83 (t, 1H), 4.21 (dd, 1H); HPLC-MScalculated for C₂₂H₁₅ClF₃NO₃ (M+H⁺) 434.1, found 434.1.

Example 73-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

Step A: 3-(Trifluoromethyl)styrene (1.70 mL, 11.5 mmol) is added to amixture of iodine (0.29 g, 1.15 mmol) and Chloramine-T (3.12 g, 11.5mmol) in acetonitrile (35 mL). The reaction mixture is stirred at roomtemperature under a nitrogen atmosphere overnight, then taken in H₂O(200 mL) and extracted with CH₂Cl₂ (3×100 mL). The combined organiclayer is washed with brine, dried over MgSO₄, concentrated and purifiedby silica gel chromatography (0˜20% EtOAc/Hexanes) to provide1-tosyl-2-(3-(trifluoromethyl)phenyl)aziridine (3.44 g, 88% yield) as acolorless oil product.

Step B: To a solution of 1-tosyl-2-(3-(trifluoromethyl)phenyl)aziridine(2.29 g, 6.71 mmol) in Et₂O (13.5 mL) are added4-(4-chlorophenoxy)aniline (1.47 g, 6.71 mmol) and LiClO₄ (0.36 g, 3.36mmol). The reaction mixture is stirred at room temperature overnight.After removal of the solvent, the crudeN-(2-(4-(4-chlorophenoxy)phenylamino)-2-(3-(trifluoromethyl)phenyl)ethyl)-4-methylbenzenesulfonamideis used in next step without further purification.

Step C: To a solution of the crude product from Step B in acetonitrile(13.5 mL) at 0° C. are added triphosgen (1.33 g, 4.47 mmol) and TEA(1.87 mL, 13.4 mmol). The reaction mixture is heated at 80° C. for 1.5h. After cooling down to room temperature, the reaction mixture is takenin H₂O (100 mL) and extracted with EtOAc (3×50 mL). The combined organiclayer is washed with brine, dried over MgSO₄, concentrated and purifiedby silica gel chromatography (0˜50% EtOAc/Hexanes) to provide the titlecompound (2.64 g, 67% yield for two steps) as a white solid product; ¹HNMR (CDCl₃, 400 MHz) δ 7.96 (d, 2H), 7.58 (d, 1H), 7.47 (t, 1H), 7.41(m, 2H), 7.36 (d, 2H), 7.23 (d, 2H), 7.19 (d, 2H), 6.83 (m, 4H), 5.22(dd, 1H), 4.37 (dd, 1H), 3.81 (dd, 1H), 2.46 (s, 3H); HPLC-MS calculatedfor C₂₉H₂₂ClF₃N₂O₄S (M+H⁺) 587.1, found 587.1.

Example 9(S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-(S)-phenyl-imidazolidine-2,4-dione

Step A: A reaction tube charged with L-phenylglycine (151.2 mg, 1.00mmol), 4-(4-chloro-phenoxy)-iodobenzene (165.3 mg, 0.50 mmol), K₂CO₃(103.7 mg, 0.75 mmol), and CuI (9.5 mg, 0.05 mmol) is purged withnitrogen. Anhydrous dimethylacetamide (0.6 mL) is added via syringe. Thereaction mixture is heated at 90° C. overnight before removal of thesolvent in vacuo. The residue is used directly in next step withoutfurther purification.

Step B: The reaction residue from step A is taken in acetic acid (5.0mL) and potassium cyanate (324.5 mg, 4.00 mmol) is added. The reactionmixture is heated at 80° C. for 1 h before removal of the solvent. Theresidue is basified with saturated NaHCO₃ aqueous solution at 0° C. andextracted with ethyl acetate. The combined ethyl acetate layer is driedover MgSO₄, concentrated, and purified by silica gel chromatography toprovide(S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-phenyl-imidazolidine-2,4-dione(49.1 mg, 26% yield for two steps) as a yellow solid product; ¹H NMR(CDCl₃, 400 MHz) δ 7.78 (br, 1H), 7.39-7.33 (m, 7H), 7.26 (d, 2H), 6.91(d, 2H), 6.89 (d, 2H), 5.48 (s, 1H); HPLC-MS calculated for C₂₁H₁₅ClN₂O₃(M+H⁺) 379.1, found 379.1.

Example 13(S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-fluoro-5-trifluoromethyl-phenyl)-oxazolidin-2-one

Step A: In a 100 mL round bottom flask is addedmethyltriphenylphosphonium bromide (2.79 g, 7.8 mmol) and anhydrousethyl ether (40 mL). The suspension is then cooled down to −78° C. andBuLi (6.77 mmol, 4.23 mL 1.6 M solution in hexane) is added dropwise.After the addition, the bright yellow mixture is warmed up to 0° C. andstirred for 30 min and cooled down to −78° C. again. To this mixture, asolution of 3-fluoro-5-trifluoromethyl-benzaldehyde (1 g, 5.2 mmol) inanhydrous ethyl ether (6 mL) is added drop by drop. After the addition,the mixture is slowly warmed up to room temperature and stirred for 14hr. The precipitate is removed by filtration and washed with ethyl ether(2×5 mL). The filtrate is concentrated by distilling off ethyl ether at±60° C. bath temperature. The resulted higher boiling point liquid ispurified by pass through a short column (silica gel) with hexane. Afterremoving the hexane under vacuum (˜150 mmHg), the resulted crude1-fluoro-3-trifluoromethyl-5-vinyl-benzene is used directly for nextstep.

Step B: (S)-(3-fluoro-5-trifluoromethyl-phenyl)-oxazolidin-2-one can beprepared from 1-fluoro-3-trifluoromethyl-5-vinyl-benzene by followingthe methods described in example 4, step A.

Step C:(S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-fluoro-5-trifluoromethyl-phenyl)-oxazolidin-2-onecan be prepared by following methods described in example 4, step B. ¹HNMR (CDCl₃, 400 MHz) δ 7.20-7.37 (m, 7H), 6.92 (d, 2H), 6.89 (d, 2H),5.42 (q, 1H), 4.84 (t, 1H), 4.20 (q, 1H); HPLC-MS calculated forC₂₂H₁₄ClF₄NO₃ (M+H⁺) 452.1, found 452.1.

Example 14(S)-3-(4-Benzyl-phenyl)-4-(3-trifluoromethyl-phenyl)-4-oxazolidin-2-one

A mixture of(S)-3-(4-bromo-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one (20mg, 0.052 mmol), 2-benzyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (17mg, 0.078 mmol), Pd(dppf)₂Cl₂ (4 mg, 0.005 mmol) and Cs₂CO₃ (34 mg,0.104 mmol) in anhydrous DMF (0.5 mL) is degassed and heated to 100° C.for 24 h. After cooling down to room temperature, the mixture is treatedwith saturated aqueous NH₄Cl solution (3 mL) and extracted with EtOAc(3×3 mL). The combined organic layers is concentrated and purified bypreparative LC/MS and preparative thin layer chromatography sequentiallyto provide the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (t, 1H),7.54 (s, 1H), 7.49 (d, 2H), 7.27 (d, 2H), 7.24 (d, 2H), 7.18 (t, 1H),7.11 (d, 2H), 7.09 (d, 2H), 5.42 (q, 1H), 4.81 (t, 1H), 4.18 (q, 1H);HPLC-MS calculated for C₂₃H₁₈F₃NO₂ (M+H⁺) 398.1, found 398.1.

Example 151-[4-(4-Chloro-phenoxy)-phenyl]-3-methyl-5-(S)-phenyl-imidazolidine-2,4-dione

To a solution of1-[4-(4-chloro-phenoxy)-phenyl]-5-(S)-phenyl-imidazolidine-2,4-dione(10.0 mg, 0.026 mmol) in anhydrous DMF (0.5 mL) are added K₂CO₃ (7.3 mg,0.052 mmol) and MeI (4.93 μL, 0.078 mmol). The reaction mixture isstirred at room temperature overnight before removal of the solvent. Theresidue is purified by preparative LC/MC to provide the title compound;¹H NMR (CDCl₃, 400 MHz) δ 7.42-7.31 (m, 7H), 7.26 (d, 2H), 6.90 (m, 4H),5.42 (s, 1H), 3.16 (s, 3H); HPLC-MS calculated for C₂₂H₁₇ClN₂O₃ (M+H⁺)393.1, found 393.1.

Example 163-[4-(4-chloro-phenoxy)-phenyl]-1-methyl-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one

To a solution of1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one(20.0 mg, 0.046 mmol) in anhydrous DMF (0.5 mL) is added NaH (2.2 mg,60% dispersion in mineral oil, 0.055 mmol) at 0° C. The reaction mixtureis stirred at room temperature for 30 minutes before MeI (8.63 μL, 0.138mmol) is added. The mixture is stirred at room temperature for 2 hoursand then partitioned between water and ethyl acetate. The organic layeris concentrated and purified by preparative LC/MC to provide the titlecompound; HPLC-MS calculated for C₂₃H₁₈ClF₃N₂O₂ (M+H⁺) 447.1, found447.1.

Example 20(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-methyl-4-phenyloxazolidin-2-one

Step A: To a 100 mL flask was added 7 mL of a 0.556M NaOH solution (3.9mmol), 3.5 mL n-propanol, 1,3-dichloro-5,5-dimethylhydantoin (394 mg,2.0 mmol), and ethyl carbamate (356 mg, 4.0 mmol). In a separate flask,potassium osmate (11 mg, 0.03 mmol) was dissolved in 0.2 mL of the NaOHsolution (0.1 mmol). To a third flask was added trans-β-methylstyrene(0.168 mL, 1.3 mmol), 1 mL n-propanol, and (DHQ)₂PHAL (23 mg, 0.03mmol). This solution was added to the first flask, followed by theosmate solution. The reaction was stirred at ambient temperature for 3h, at which point NaOH (160 mg, 4 mmol) was added and the reaction wasstirred for an additional h. The reaction was quenched with a slightexcess of sodium sulfite, and diluted with water and ethyl acetate. Theaqueous phase was extracted once with ethyl acetate and the organicphases combined, washed with brine, dried (MgSO₄), and concentrated.Flash chromatography (0-30% ethyl acetate/hexanes) afforded 195 mg (84%)of the product as a 3.4:1 mixture of regioisomers of the oxazolidinones.

Step B: The oxazolidinone from Step A was placed into a 20 mL reactionvessel and subsequently treated with 1-(4-iodophenoxy)-4-chlorobenzene(1.1 eq), copper iodide (0.1 eq), N,N′-dimethylethylenediamine (0.2 eq),and potassium carbonate (2 eq). The reaction vessel was capped,evacuated and back-filled with nitrogen twice, and heated to 100° C.overnight. The reaction was subsequently cooled to room temperature,quenched with excess 1 M HCl, extracted with ethyl acetate, washed withbrine, then dried over MgSO₄, and concentrated. Flash chromatography(0-30% ethyl acetate/hexanes) gave the title compounds. 58 mg isolated(61% overall yield) as a white solid. Example 20: ¹H NMR (acetone-d6) δ(ppm) 7.46-7.49 (m, 4H), 7.32-7.42 (m, 5H), 6.93-6.98 (m, 4H), 5.24 (d,1H, J=6.6 Hz), 4.46 (p, 1H, J=6.3 Hz), 1.58 (d, 3H, J=6.2 Hz). HPLC-MScalculated C22H18ClNO3 (M+H⁺): 380.8, found: 380.8. Regioisomer: ¹H NMR(acetone-d6) δ (ppm) 7.52-7.58 (m, 4H), 7.39-7.50 (m, 7H), 7.02-7.11 (m,4H), 5.27 (d, 1H, J=6.8 Hz), 4.48 (p, 1H, J=6.3 Hz), 1.44 (d, 3H, J=6.1Hz). HPLC-MS calculated C₂₂H₁₈ClNO₃ (M+H⁺): 380.8, found: 380.8.

Example 26(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)-oxazolidin-2-one

Step A: (4S,5R)-ethyl4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidine-5-carboxylate (650 mg,2.1 mmol), was dissolved in 8 mL dry MeOH under nitrogen and cooled to0° C. NaBH₄ (162 mg, 4.3 mmol) was added and the reaction was stirred 1h, as judged complete by TLC. Saturated ammonium chloride was addedcarefully to quench, and the suspension was diluted with water and ethylacetate. The organic phase was washed with brine, dried (MgSO₄), andconcentrated to give 380 mg of a colorless oil that was used withoutpurification.

Step B: To the alcohol from Step A in 3 mL DMF was added imidazole (130mg, 1.91 mmol) and TBSCl (160 mg, 1.05 mmol). The reaction was stirredat ambient temperature overnight, at which point saturated NaHCO₃ wasadded to quench. Aqueous extracted once with ethyl acetate and theorganic was dried (MgSO₄), and concentrated. Flash chromatography (0-30%ethyl acetate/hexanes) provided 241 mg (67%) of a white solid.

Step C: Reaction performed as described in Example 20.

Step D: To the TBS ether (13 mg, 0.02 mmol) in THF at 0° C. was addedTBAF (0.034 mL, 0.03 mmol). The reaction was stirred for 30 min at thistemperature as judged complete by TLC. Saturated ammonium chloride wasadded to quench, followed by dilution with water and ethyl acetate. Theorganic phase was washed with brine, dried (MgSO₄), and concentrated.Flash chromatography (0-40% ethyl acetate/hexanes) gave 8 mg (80%) ofthe title compound as a colorless oil. ¹H NMR (CDCl₃) δ (ppm) 7.51-7.61(m, 4H), 7.30 (d, 2H, J=9.0 Hz). 7.25 (d, 2H, J=8.9 Hz), 6.88 (t, 4H,J=9.1 Hz), 5.43 (d, 1H, J=6.3 Hz), 4.39-4.42 (m, 1H), 4.08 (dd, 1H,J=12.8, 3.2 Hz), 3.84 (dd, 1H, J=12.8, 3.0 Hz). HPLC-MS calculatedC₂₃H₁₇ClF₃NO₄ (M+H⁺): 464.1, found: 464.1.

Example 28(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(methoxymethyl)-4-phenyloxazolidin-2-one

To(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one(14 mg, 0.035 mmol) in THF (1 mL) was added NaH (˜5 mg) and the reactionwas stirred for 10 min. at room temperature. Iodomethane (˜0.01 mL) wasadded and the reaction was stirred for an additional 2 h. NaHCO₃ aqueoussolution was added to quench, followed by dilution with water and ethylacetate. The organic phase was washed with brine, dried (MgSO₄), andconcentrated. Flash chromatography (0-30% ethyl acetate/hexanes) yielded8 mg (57%) of the title compound as a colorless oil. ¹H NMR (CDCl₃) δ(ppm) 7.23-7.32 (m, 7H), 7.16-7.19 (m, 2H), 6.78-6.82 (m, 4H), 5.16 (d,1H, J=5.7 Hz), 4.36 (dd, 1H, J=9.3, 3.9 Hz), 3.63 (ddd, 2H, J=18.4,11.0, 4.1), 3.41 (s, 3H). HPLC-MS calculated C₂₃H₂₀ClNO₄ (M+H⁺): 410.1,found: 410.1.

Example 30((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methylisopropylcarbamate

To(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one(33 mg, 0.08 mmol) in 0.3 mL DMF was added isopropyl isocyanate (0.015mL, 0.16 mmol). The reaction was stirred for 3 h at room temperatureuntil reaction completed as judged by TLC. Water and ethyl acetate wereadded and the phases separated. The organic phase was washed with brine,dried (MgSO₄), and concentrated. 13 mg (33%) of the title compound wasobtained as a white solid after Prep-LC purification (10-90Acetonitrile/water (0.05% ammonium acetate). ¹H NMR (CDCl₃) δ (ppm)7.30-7.39 (m, 7H), 7.23-7.26 (m, 2H), 6.84-6.90 (m, 4H), 5.14 (d, 1H,J=5.6 Hz), 4.67 (d, 1H, J=7.2 Hz), 4.34-4.53 (m, 3H), 3.77-3.85 (m, 1H),1.17 (d, 3H, J=6.5 Hz), 1.13 (d. 3H, J=6.5 Hz). HPLC-MS calculatedC₂₆H₂₅ClN₂O₅ (M+H⁺): 481.2, found: 481.1.

Example 332-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione

To(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one(161 mg, 0.4 mmol) and triethylamine (0.17 mL, 1.2 mmol) indichloromethane (3 mL) was added tosyl chloride (93 mg, 0.48 mmol). Thereaction mixture was stirred for 17 h at ambient temperature andquenched with NaHCO₃ aqueous solution. Water and dichloromethane wereadded. The organic phase was separated, dried (MgSO₄), and concentrated.Flash chromatography (0-30% ethyl acetate/hexanes) yielded 196 mg (89%)of the title compound as a colorless oil that crystallized on standing.¹H NMR (CDCl₃) δ (ppm) 7.85-7.88 (m, 2H), 7.75-7.78 (m, 2H), 7.22-7.31(m, 9H), 6.83-6.88 (m, 4H), 5.21 (d, 1H, J=5.4 Hz), 4.72 (dd, 1H,J=11.5, 5.9 Hz), 4.16 (d, 2H, J=6.0 Hz). HPLC-MS calculated C₃₀H₂₁ClN₂O₅(M+H⁺): 525.1, found: 525.1.

Example 34(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-phenyl-oxazolidin-2-one

To(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one(44 mg, 0.11 mmol) and triethylamine (0.046 mL, 0.33 mmol) indichloromethane (1.5 mL) at 0° C. was added mesyl chloride (0.012 mL,0.15 mmol). The reaction mixture was stirred at this temperature for 20min until reaction complete as judged by TLC, and then was quenched withNaHCO₃ aqueous solution. The aqueous layer was extracted (2×dichloromethane) and the organics combined, dried (MgSO₄), andconcentrated. The oil was taken up in 2 mL DMF and treated with NaN₃ (14mg, 0.2 mmol) at 70° C. for 5 h (monitored by analytical LC/MS). Thereaction was cooled to room temperature, and then quenched with water.Ethyl acetate was added and the organic was washed with brine, dried(MgSO₄), and concentrated. The oil was re-dissolved in THF/water (10:1,1 mL) and treated with triphenylphosphine (34 mg, 0.12 mmol). Thereaction was stirred at room temperature overnight and thenconcentrated. Flash chromatography (0-5% MeOH/dichloromethane) gave 35mg (80%, 3 steps) of a the title compound as colorless oil thatcrystallized on standing. ¹H NMR (acetone-d₆) δ (ppm) 7.49-7.53 (m, 2H),7.30-7.46 (m, 7H), 6.92-6.97 (m, 4H), 5.48 (d, 1H, J=4.8 Hz), 4.55 (dd,1H, J=9.5, 4.7 Hz), 3.64 (dd, 2H, J=4.9, 1.6 Hz). HPLC-MS calculatedC₂₂H₁₉ClN₂O₃ (M+H⁺): 395.1, found: 395.1.

Example 35N-((4S,5S)-3-(4-(4-chloro-phenoxy)-phenyl)-2-oxo-4-phenyl-oxazolidin-5-ylmethyl)-methanesulfonamide

To a solution of(4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-phenyl-oxazolidin-2-one(14 mg, 0.035 mmol) and triethylamine (0.01 mL, 0.07 mmol) indichloromethane (0.4 mL) at 0° C. was added mesyl chloride (0.005 mL,0.05 mmol). The reaction mixture was stirred for 10 min and was thenquenched with saturated NaHCO₃ aqueous solution. Water anddichloromethane was added and the organic was washed with brine, dried(MgSO₄), and concentrated. Purification by prep-LC (10-90%Acetonitrile/water (0.05% ammonium acetate) gave 5 mg (31%). ¹H NMR(acetone-d₆) δ (ppm) 7.45-7.51 (m, 4H), 7.32-7.42 (m, 5H), 6.94-6.97 (m,4H), 6.66 (t, 1H, J=6.6 Hz), 5.56 (d, 1H, J=5.6 Hz), 4.51, (dd, 1H,J=10.1, 4.7 Hz), 3.59-3.72 (m, 2H), 3.04 (s, 3H). HPLC-MS calculatedC₂₃H₂₁ClN₂O₅S (M+H⁺): 473.1, found: 473.1.

Example 38(4S,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4-(4-chloro-phenoxy)-phenyl)-4-phenyl-oxazolidin-2-one

A stirring solution of the oxazolidinone (31 mg, 0.1 mmol) indichloromethane was treated with the boronic acid (50 mg, 0.2 mmol),triethylamine (40 μL, 0.3 mmol), and copper II acetate (36 mg, 0.2mmol). Stirred at room temperature until complete, then filtered throughcelite, diluted with ethyl acetate, washed with 1 M HCl, then dried overmagnesium sulfate, filtered and concentrated. Purified on silica gel(10-30% ethyl aceate/hexanes) to give the title compound (5 mg, 10%) asa colorless oil. ¹H NMR (CDCl₃) δ (ppm) 7.24-7.37 (m, 9H), 6.86-6.89 (m,4H), 5.26 (d, 1H, J=4.7 Hz), 4.35 (d, 1H, J=3.5 Hz), 3.95 (dd, 1H,J=11.6, 3.9 Hz), 3.86 (d, 1H, J=11.5 Hz), 0.89 (s, 9H,), 0.12 (s, 6H).HPLC-MS calculated C₂₈H₃₂ClNO₄Si (M+H⁺): 510.2, found: 510.2.

Example 39 and Example 42 (4S,5R)-ethyl3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidine-5-carboxylate;(4S,5S)-ethyl3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidine-5-carboxylate

Step A: In a 500 mL round bottom flask was placed sodium hydroxide (1.19g, 29.8 mmol) and water (70 mL). Once the sodium hydroxide haddissolved, a 2.0 mL aliquot was removed and was used to dissolvepotassium osmate (213 mg, 0.58 mmol, 6 mol %) in a 4 dram vialcontaining a stir bar. Then, n-propanol (50 mL) was added to thehydroxide solution, followed by addition of t-butyl carbamate (3.48 g,29.8 mmol), and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.93g, 14.9 mmol). The mixture was stirred vigorously at 0° C. To a separateflask was dissolved (E)-ethyl 3-(3-fluorophenyl)acrylate (1.87 g, 9.6mmol), (DHQ)₂PHAL (450 mg, 0.58 mmol, 6 mol %) in n-propanol (25 mL).This solution was then added to the previously prepared solution, whichwas subsequently followed by addition of the osmate solution. After 2 h,the reaction was quenched with sodium sulfite (slight excess), and water(50 mL). The contents were then partitioned with ethyl acetate and theaqueous layer was removed and extracted with ethyl acetate (2×100 mL).The combined organics were then washed with brine (50 mL), dried overmagnesium sulfate, filtered, concentrated in vacuo, and then purified onsilica gel with 30% ethyl acetate/70% hexanes to give the product (2.68g, 85%) as a white solid as a 3:1 mixture of regioisomers. HPLC-MScalculated for C₁₆H₂₂FNO₅ (M+Na⁺) 350.2, found 350.1, C₁₁H₁₄FNO₃(M-Boc+H⁺) 227.1, found 227.1.

Step B: The product from step A was dissolved in dichloromethane (24 mL)and treated with a 4.0M solution of HCl in dioxane (12 mL) and stirredovernight. The solvents were evaporated in vacuo, and the residue wasthen suspended in tetrahydrofuran (40 mL) and treated withdiisopropylethylamine (DIEA) (4.23 mL, 24 mmol) followed bycarbonyldiimidazole (1.64 g, 10.1 mmol). The mixture was heated toreflux for 3 h, and was then cooled to room temperature, diluted withethyl acetate (30 mL) and water (30 mL) and then acidified with 0.5 MHCl (15 mL). The layers were separated, and the aqueous layer wasextracted with ethyl acetate (2×50 mL). The combined organics were driedover magnesium sulfate, filtered and concentrated. The crude mixture waspurified on silica gel with methanol/dichloromethane (3-7% methanolgradient) to give 1.2 g (88%) of product as a mixture of regioisomers.HPLC-MS calculated for C₁₂H₁₂FNO₄ (M+H⁺) 254.1, found 254.0.

Step C: To a 20 mL reaction tube fitted with a screw cap was added(4S,5R)-ethyl 4-(3-fluorophenyl)-2-oxazolidinone-5-carboxylate (120 mg,0.47 mmol) and acetonitrile (2.5 mL). 1-chloro-4-(4-iodophenoxy)-benzene(196 mg, 0.60 mmol) was then added, followed by copper iodide (25 mg,0.13 mmol), N,N′-dimethylethylenediamine (0.03 mL, 0.28 mmol), andpotassium carbonate (162 mg, 1.18 mmol). The system was sealed andevacuated and back-filled with nitrogen three times, then heated to 100°C. for 4 h. The reaction was cooled to room temperature, quenched with1M HCl (3 mL) and extracted with ethyl acetate. The combined organicswere washed once with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification on silica gel (20% ethyl acetate/80%hexanes) gave 76.1 mg of (4S,5R)-ethyl3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidine-5-carboxylate(Example 39) and 27.5 mg of (4S,5S)-ethyl3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidine-5-carboxylate(Example 42) (48% overall yield). Trans-isomer: ¹H NMR (d₆ acetone) δ(ppm) 7.54 (d, J=9.1 Hz, 2H), 7.53-7.47 (m, 1H), 7.38 (d, J=8.9 Hz, 2H),7.37-7.31 (m, 2H), 7.19-7.14 (m, 1H), 7.00-6.97 (m, 4H), 5.83 (d, J=5.1Hz, 1H), 5.00 (d, J=5.1 Hz, 1H), 4.37-4.30 (m, 2H), 1.34 (t, J=7.1 Hz,3H); HPLC-MS calculated C₂₄H₁₉ClFNO₅ (M+H⁺): 456.1, found: 456.0.Cis-isomer: ¹H NMR (d₆ acetone) δ (ppm) 7.55 (d, J=9.1 Hz, 2H),7.46-7.41 (m, 1H), 7.38 (d, J=8.9 Hz, 2H), 7.21 (d, J=7.8 Hz, 1H),7.17-7.01 (m, 2H), 7.00-6.97 (m, 4H), 6.13 (d, J=9.4 Hz, 1H), 5.61 (d,J=9.4 Hz, 1H), 3.88-3.82 (m, 1H), 3.75-3.68 (m, 1H), 0.92 (t, J=7.1 Hz,3H); HPLC-MS calculated C₂₄H₁₉ClFNO₅ (M+H⁺): 456.1, found: 456.0.

Example 41(S)-4-(4-(4-chlorophenoxy)phenyl)-5-(3-fluorophenyl)morpholin-3-one

Step A: was performed as described in Example 20 to give tert-butyl(S)-1-(3-fluorophenyl)-2-hydroxyethylcarbamate (27% yield). HPLC-MScalculated for C₁₃H₁₈FNO₃ (M+Na⁺) 278.2, found 278.1, C₈H₁₀FNO(M-Boc+H⁺) 155.1, found 155.1.

Step B: Tert-butyl (S)-1-(3-fluorophenyl)-2-hydroxyethylcarbamate (256mg, 1.0 mmol) was dissolved in acetonitrile (10 mL) and treated withcesium carbonate (391 mg, 1.2 mmol) and ethyl bromoacetate (0.14 mL,1.25 mmol). The mixture was heated to 100° C. for 30 min, then cooled toroom temperature, acidified, and extracted with ethyl acetate.Purification on silica gel (15%-40% ethyl acetate/hexanes) gave 69 mg oftert-butyl(S)-2-((ethoxycarbonyl)methoxy)-1-(3-fluorophenyl)ethylcarbamate as acolorless glass. HPLC-MS calculated for C₁₇H₂₄FNO₅ (M+H⁺) 342.2, found342.1.

Step C: In a 10 mL round bottom flask was added tert-butyl(S)-2-((ethoxycarbonyl)methoxy)-1-(3-fluorophenyl)ethylcarbamate (69 mg,0.2 mmol), dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL).The solution was stirred at room temperature overnight then concentratedto dryness. The residue was then dissolved in tetrahydrofuran (2 mL) andsubsequently treated with DIEA (0.5 mL) and potassium carbonate (excess)and heated 50° C. for 1 h. Upon cooling to room temperature, thereaction solution was diluted with water (3 mL) and extracted with ethylacetate. The combined organics were dried over magnesium sulfate,filtered and concentrated. Purification on silica gel (40% ethylacetate/hexanes) gave (S)-5-(3-fluorophenyl)morpholin-3-one (37 mg, 95%)as a colorless oil. HPLC-MS calculated for C₁₀H₁₀FNO₂ (M+H⁺) 196.2,found 196.1.

Step D: was performed according to the method (Step C) described inExample 39/42 to give the title compound (53%) as a colorless oil. ¹HNMR (d₆ acetone) δ (ppm) 7.39-7.29 (m, 5H), 7.26-7.21 (m, 2H), 7.06-7.01(m, 1H), 6.99-6.96 (m, 2H), 6.94-6.90 (m, 2H), 5.26 (app t, J=3.8 Hz,1H), 4.47 (d, J=16.6 Hz, 1H), 4.35 (dd, J=12.0, 3.8 Hz, 1H), 4.16 (d,J=16.5 Hz, 1H), 4.02 (dd, J=11.9, 3.9 Hz, 1H); HPLC-MS calculatedC₂₂H₂₂ClFNO₃ (M+H⁺): 398.1, found: 398.0.

Example 48(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one

The title compound was obtained as a colorless oil from1-((E)-3-(benzyloxy)prop-1-enyl)-3,5-difluorobenzene by the same methodthat is described for Example 39.(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one(Example 96) was placed into a 25 mL round bottom flask and dissolved in7 mL ethanol:ethyl acetate (1:1) and treated with palladium on carbon(10% by weight, 73 mg). The vessel was sealed with a rubber septum andcharged with hydrogen. The reaction was stirred for 2 h, then filteredon celite, evaporated to dryness and purified on silica gel (20-30%ethyl acetate/hexanes) to give the title compound as a colorless oilthat solidified on standing. ¹H NMR (acetone-d₆) δ (ppm) 7.53 (d, J=9.1Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.21-7.16 (m, 2H), d, J=6.15 Hz, 2H),7.02-6.93 (m, 5H), 5.58 (d, J=5.4 Hz, 1H), 4.55 (t, J=5.8 Hz, 1H), 4.45(ddd, J=5.6, 3.7, 3.6), 3.97 (ddd, J=12.3, 5.6, 3.8 Hz, 1H), 3.90 (ddd,J=12.3, 5.6, 3.8 Hz, 1H); HPLC-MS calculated C₂₂H₁₆ClF₂NO₄ (M+H⁺):432.1, found: 432.0.

Example 49(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-hydroxyphenyl)oxazolidin-2-one

(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one(Example 91) was dissolved in dichlormethane, cooled to −78° C., andtreated with boron tribromide (1M solution, 2.1 eq). After 10 min, thecooling bath was removed, and the reaction mixture is stirred for 1 h.The reaction was then quenched with water, extracted with ethyl acetate,dried over magnesium sulfate, filtered, concentrated, and purified onsilica gel (2-5% methanol/dichlormethane) to give the title compound. ¹HNMR (acetone-d₆) δ (ppm) 8.36 (s, 1H), 7.42 (d, J=9.1 Hz, 2H), 7.23 (d,J=9.0 Hz, 2H), 7.09 (t, J=7.9 Hz, 1H), 6.85-6.81 (m, 4H), 6.77 (d, J=7.6Hz, 1H), 6.74 (m, 1H), 6.67 (dd, J=8.1, 2.4 Hz, 1H), 5.39 (d, J=5.2 Hz,1H), 4.49 (t, J=5.9 Hz, 1H), 4.36 (ddd, J=5.6, 3.7, 3.4), 3.96 (ddd,J=12.4, 5.7, 3.6 Hz, 1H), 3.85 (ddd, J=12.3, 5.6, 3.8 Hz, 1H); HPLC-MScalculated C₂₂H₁₈ClNO₅ (M+H⁺): 411.1, found: 410.0.

Example 52(4S,5S)-5-((2-(dimethylamino)ethylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)oxazolidin-2-one

Step A:(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one(Example 91) (130 mg, 0.31 mmol) was dissolved in dichloromethane andtreated with triethylamine (TEA, 0.1 mL, 0.62 mmol) and was then cooledto 0° C. Methanesulfonyl chloride (0.025 mL, 0.32 mmol) was then addedand after 30 min, the reaction was quenched with 3 mL 1M HCl and dilutedwith dichloromethane. After extraction with dichloromethane, theorganics were combined, dried over magnesium sulfate, filtered andconcentrated. The product was carried forward without purification.

Step B: The product from Step A (0.04 mmol) was dissolved in DMF (0.5mL) and treated with N,N-dimethylethylene diamine (0.4 mmol) at 100° C.overnight. The cooled solution was subsequently purified by preparatoryLC-MS (C-18, 10-90% ACN/water (0.05% TFA) to give the title compound asa colorless oil. ¹H NMR (acetone-d₆) δ (ppm) 7.53-7.49 (m, 2H),7.38-7.36 (m, 2H), 7.30 (t, J=7.9 Hz, 1H), 7.06 (t, J=2.0 Hz, 1H), 7.01(d, J=7.7 Hz, 1H), 6.98-6.94 (m, 4H), 6.90-6.88 (m, 1H), 5.61 (d, J=5.6Hz, 1H), 4.89 (ddd, J=6.5, 5.6, 5.6 Hz, 1H) 3.93-3.83 (m, 2H), 3.89-3.74(m, 9H), 3.10 (br s, 6H), 2.10-2.05 (obscured by solvent); HPLC-MScalculated C₂₇H₃₀ClN₃O₄ (M+H⁺): 496.2, found: 496.2.

Example 64(4S,5S)-5-((4-acetylpiperazin-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one

Step A: (4S,5R)-methyl4-(3,5-difluorophenyl)-2-oxooxazolidine-5-carboxylate (preparedaccording to Example 39 from (E)-methyl 3-(3,5-difluorophenyl)acrylate)(11 mmol) was dissolved in methanol (70 mL) and cooled to 0° C. NaBH₄(407 mg, 11 mmol) was then added and the reaction mixture was stirredfor 30 min. and then was quenched with 0.1 M HCl (20 mL) andconcentrated by 80-90% on rotary evaporator. The contents were thenextracted with ethyl acetate. The combined organics were washed withbrine, then dried over magnesium sulfate, filtered and concentrated.Carried forward without purification.

Step B: The product from Step A was dissolved in dichloromethane (to aconcentration of 0.2 M) and treated with 3,4-dihydro-2H-pyran (1.2 eq)and catalytic p-toluenesulfonic acid (0.1 eq). After 2 h the reactionwas quenched with aq. sodium bicarbonate and diluted withdichloromethane and transferred to an extraction funnel. The organiclayer was removed, the aqueous layer was extracted once withdichloromethane, and the combined organics were dried, filtered,concentrated and purified on silica gel with 40% ethylacetate/hexanes→50% ethyl acetate/hexanes to give the pure product.

Step C: The reaction was performed as described for Example 39 (Step C)using 4-chloro-1-iodobenzene instead of1-(4-iodophenoxy)-4-chlorobenzene. The crude product was purified onsilica gel (30% ethyl acetate/hexanes) to give the desired product.

Step D: The THP group was removed under standard conditions (T. W.Greene and P. G. M. Wuts, Protective groups in Organic Synthesis,1999.).

Steps E and F: The title compound was prepared by mesylation followed bynucleophilic replacement with 1-acetylpiperizine using the methodsdescribed for Example 52 to give the product as a colorless oil. ¹H NMR(acetone-d6) δ (ppm) 7.51-7.49 (m, 2H), 7.35-7.32 (m, 2H), 7.24-7.22 (m,2H), 7.00 (tt, J=9.1, 2.3 Hz, 1H), 5.63 (d, J=6.5 Hz, 1H), 4.65 (ddd,J=ddd, J=6.5, 5.4, 3.2 Hz, 1H), 3.81-3.58 (m, 5H), 3.28-3.16 (m, 4H),2.07 (part. obs. s, 3H); HPLC-MS calculated C₂₂H₂₂ClF₂N₃O₃ (M+H⁺):450.1, found: 450.1.

Example 72(4S,5R)-5-((benzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one

(4S,5R)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)-oxazolidin-2-one(0.08 mmol), prepared according to the method described for Example 64,in dichloromethane (1 mL) was treated with benzyltrichloroacetimidate(0.09 mmol) and catalytic trifluoromethane sulfonic acid. The reactionwas stirred overnight, and was then purified on silica gel (10-30% ethylacetate/hexanes) to give the title compound. ¹H NMR (acetone-d6) δ (ppm)7.82 (s, 1H), 7.74 (d, J=7.6 Hz, 1H) 7.68 (d, J=7.7 Hz, 1H), 7.65-7.61(m, 1H), 7.54-7.52 (m, 2H), 7.37-7.28 (m, 6H), 5.72 (d, J=5.3 Hz, 1H),4.71-4.62 (m, 3H), 3.95 (d, J=3.8 Hz, 2H); HPLC-MS calculatedC₂₄H₁₉ClF₃NO₃ (M+H⁺): 462.1, found: 461.9.

Example 83(4S,5R)-3-(5-(4-chlorophenoxy)pyrazin-2-yl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one

(4S,5R)-4-(3-(trifluoromethyl)phenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-oxazolidin-2-one(prepared as in Example 64, Steps A and B) (54 mg, 0.16 mmol) was addedto a 10 mL reaction vessel with a screw cap and charged withacetonitrile (0.5 mL), 2-(4-chlorophenoxy)-5-bromopyrazine (47 mg, 0.16mmol), copper (I) iodide (14 mg, 0.074 mmol),N,N′-dimethylethylenediamine (0.014 mL, 0.15 mmol), and potassiumcarbonate (44 mg, 0.32 mmol). The vessel was sealed, evacuated andback-filled with nitrogen twice, and then heated to 110° C. in amicrowave for 30 min. The reaction mixture was cooled to roomtemperature, quenched with 1 M HCl, and extracted with ethyl acetate.The organic layer was dried, filtered and concentrated to give the crudeintermediate which was immediately dissolved in methanol (5 mL) andtreated with excess toluenesulfonic acid for 1 h. The reaction wasquenched with 1 mL triethylamine, then concentrated to dryness andpurified on silica gel (30% ethyl acetate/hexanes) to give the titlecompound as a white solid. ¹H NMR (acetone-d₆) 600 MHz δ (ppm) 8.91 (d,J=1.3 Hz, 1H), 8.05 (d, 1.3 Hz, 1H), 7.83 (s, 1H), 7.76 (d, J=7.6 Hz,1H), 7.67 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.8 Hz,2H), 7.18 (d, J=8.8 Hz, 2H), 5.86 (d, J=5.0 Hz, 1H), 4.61 (ddd, J=5.4,3.5, 3.0, 1H), 4.58 (t, J=5.7 Hz, 1H), 4.02 (ddd, J=12.4, 5.5, 3.5 z,1H), 3.94 (ddd, J=12.3, 5.9, 3.5 Hz, 1H); HPLC-MS calculatedC₂₁H₁₅ClF₃N₃O₄S (M+H⁺): 466.1, found 466.1.

Example 84(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one

(4S,5R)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one(from Example 72) was converted into(4S,5S)-5-(azidomethyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-oneas described in Example 34. The azide (0.076 mmol) was then dissolved int-butanol:water (2:1, 0.5 mL) and treated with 3-fluorophenylacetylene(0.076 mmol), followed by copper (II) sulfate pentahydrate (0.4 mg) andsodium ascorbate (0.75 mg). After stirring for 2 h, the reaction mixturewas quenched with water and extracted with ethyl acetate, dried overmagnesium sulfate, filtered and concentrated. Purification on silica gel(30% ethyl acetate/hexanes) gave the title compound as a colorless oil.¹H NMR (acetone-d6) δ (ppm) 8.57 (s, 1H), 7.88 (s, 1H), 7.79 (d, J=7.7Hz, 1H), 7.72-7.70 (m, 2H), 7.67-7.63 (m, 2H), 7.50-7.44 (m, 3H),7.30-7.28 (m, 2H), 7.11 (td, J=8.5, 2.3 Hz, 1H), 5.81 (d, J=5.2 Hz, 1H),5.22-5.16 (m, 2H), 5.07 (ddd, J=5.5, 5.5, 4.4 Hz, 1H), 4.73-4.64 (m,3H), 4.01 (d, J=3.6 Hz, 2H); HPLC-MS calculated C₂₅H₁₇ClF₄N₄O₂ (M+H⁺):517.1, found: 517.1.

Example 87(4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((3-phenyl-1H-pyrazol-1-yl)methyl)oxazolidin-2-one

Same as Example 73 by treating 3-phenyl-1H-pyrazole with 1 eq. of sodiumhydride in dimethylformamide followed by addition of the correspondingmesylate, prepared using the methods described in Example 52, to givethe title compound as a colorless oil. ¹H NMR (acetone-d6) δ (ppm) 7.82(d, J=2.3 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.76-7.74 (m, 2H), 7.71 (d,J=7.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.42-7.40(m, 2H), 7.36-7.33 (m, 2H), 7.28-7.26 (m, 2H), 7.19-7.18 (m, 2H), 5.90(d, J=4.7 Hz, 1H), 4.95 (q, J=4.6 Hz, 1H), 4.85 (dd, J=14.6, 4.6 Hz,1H), 4.79 (dd, J=14.6, 4.7 Hz, 1H); HPLC-MS calculated C₂₆H₁₉ClF₃N₃O₂(M+H⁺): 498.1, found: 498.1.

Example 88 tert-butyl(R)-1-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methylcarbamoyl)-2-methylpropylcarbamate

To a stirred solution of Boc-D-valine (12 mg, 0.06 mmol), HATU (22 mg,0.06 mmol), and DIEA (29 μL, 0.16 mmol) in acetonitrile (0.2 mL) wasadded the amine (20 mg, 0.05 mmol) in 0.1 mL acetonitrile. The reactionmixture was stirred 3 h as judged complete by TLC, and was then dilutedwith saturated aq. NH₄Cl and ethyl acetate. The organic was washed withbrine, dried over magnesium sulfate, filtered and concentrated. Purifiedon silica gel (0-5% methanol/dichloromethane) to give the title compound(30 mg, 100%) as a colorless oil. ¹H NMR (CDCl₃) δ (ppm) 7.34-7.37 (m,4H), 7.28-7.33 (m, 3H), 7.22-7.25 (m, 2H), 6.83-6.88 (m, 4H), 6.58 (t,1H, J=6.1 Hz), 5.12 (d, 1H, J=7.2 Hz), 4.89 (d, 1H, J=6.8 Hz), 4.42(ddd, 1H, J=7.3, 3.8, 3.8 Hz), 3.93-4.00 (m, 2H), 3.59 (d, 1H, J=14.1Hz), 2.19 (sextet, 1H, J=6.8 Hz), 1.38 (s, 9H), 0.97 (d, 3H, J=6.8 Hz),0.90 (d, 3H, J=6.8 Hz). HPLC-MS calculated C₃₂H₃₆ClN₃O₆ (M+H⁺): 594.2,found: 594.2.v

Example 89(2R)—N-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methyl)-2-amino-3-methylbutanamide

TFA (20 μL) was added to a cooled (0° C.) solution of the Boc-amine (25mg, 0.04 mmol) in dichloromethane (1 mL). The reaction was stirred 30min as judged complete by TLC, and quenched with saturated NaHCO₃. Thesolution was diluted with ethyl acetate, washed with brine, dried overmagnesium sulfate, filtered and concentrated. HPLC purification (0-90%acetonitrile/water) gave the title compound (11 mg, 53%) as a whitefilm. ¹H NMR (CDCl₃) δ (ppm) 8.18 (br s, 1H), 7.21-7.37 (m, 9H),6.83-6.86 (m, 4H), 5.13 (d, 1H, J=6.3 Hz), 4.46-4.50 (m, 1H), 3.82-3.89(m, 1H), 3.62-3.68 (m, 1H), 3.48 (br s, 1H), 2.31-2.39 (m, 1H), 1.0 (d,3H, J=7.0 Hz), 0.86 (d, 3H, J=6.9 Hz). HPLC-MS calculated C₂₇H₂₈ClN₃O₄(M+H⁺): 494.2, found: 494.2.

Example 99(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(morpholine-4-carbonyl)-4-phenyl-oxazolidin-2-one

A solution of (4S,5R)-morpholin-2-oxo-4-phenyloxazolidine-5-carboxamide(obtained by the method described in Example 39 from(E)-1-morpholino-3-phenylprop-2-en-1-one) (131 mg, 0.47 mmol), aryliodide (155 mg, 0.47 mmol), CuI (14 mg. 0.07 mmol), and potassiumcarbonate (118 mg, 0.85 mmol) in dry acetonitrile (0.6 mL) was purgedwith nitrogen in a tube fitted with a screw-cap. The diamine (15 μL,0.14 mmol) was added and the reaction was heated to 100° C. withstirring overnight. The reaction mixture was cooled, diluted with ethylacetate, filtered through a short plug of silica and concentrated.Purified on silica gel (0-40% ethyl aceate/hexanes) to give the titlecompound as a white solid. ¹H NMR (CDCl₃) δ (ppm) 7.33-7.37 (m, 7H),7.23-7.27 (m, 2H), 6.85-6.91 (m, 4H), 6.09 (d, 1H, J=5.8 Hz), 4.87 (d,1H, J=5.8 Hz), 3.81-3.86 (m, 1H), 3.67-3.78 (m, 5H), 3.51-3.57 (m, 1H),3.42-3.49 (m, 1H). HPLC-MS calculated C₂₆H₂₃ClN₂O₅ (M+H⁺): 479.1, found:479.1.

Example 101(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((phenylthio)methyl)oxazolidin-2-one

((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate (0.3 mmol, prepared by the methods described in example34) was dissolved in ethanol (1.5 mL) and treated with benzenethiol (0.6mmol) and triethylamine (0.6 mmol). The reaction mixture was heated to75° C. for 8 h, then was cooled to room temperature, diluted with ethylacetate, washed with 1M HCl and then purified on silica gel (10-30%ethyl acetate/hexanes) to give the title compound as a colorless oil. ¹HNMR (CDCl₃) δ (ppm) 7.31-7.37 (m, 5H), 7.24-7.29 (m, 5H), 7.08 (d, 1H,J=7.7 Hz), 6.97-7.04 (m, 2H), 6.86-6.91 (m, 4H), 5.21 (d, 1H, J=4.0 Hz),(ddd, 1H, J=8.4, 4.0, 4.0 Hz), 3.46 (dd, 1H, J=14.2, 3.9 Hz), 3.22 (dd,1H, J=14.2, 8.7 Hz). HPLC-MS calculated C₂₈H₂₁ClFNO₃S (M+H⁺): 506.1,found 506.1.

Example 106(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((phenylsulfonyl)methyl)oxazolidin-2-one

(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((phenylthio)methyl)oxazolidin-2-one(Example 101, 0.3 mmol) was dissolved in dichloromethane (12 mL) andtreated with m-chloroperbenzoic acid (77%, 1.2 mmol, 4 eq) at roomtemperature for 1 h. The reaction was diluted with dichloromethane andwashed with aq. Sodium bicarbonate solution and then a solution ofsodium metabisulfite (2×). The organic layer was dried over magnesiumsulfate, filtered and concentrated to dryness. The product was purifiedon silica gel (30% ethyl acetate/hexanes) to give the title compound asa white solid. ¹H NMR (acetone-d₆) δ (ppm) 7.95 (d, J=7.5 Hz, 2H),7.79-7.75 (m, 1H), 7.68-7.64 (m, 2H), 7.49-7.44 (m, 3H), 7.38-7.31 (m,4H), 7.16-7.11 (dt, J=8.5, 2.6 Hz, 1H), 6.97-6.93 (m, 4H), 5.61 (d,J=5.6 Hz, 1H), 4.81 (dd, J=11.9, 5.3 Hz, 1H), 4.14-4.02 (m, 2H); HPLC-MScalculated C₂₈H₂₁ClFNO₅S (M+H⁺) 538.1, found 538.1.

Example 109(4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(chloromethyl)-4-(3-fluorophenyl)oxazolidin-2-

To a solution of the mesylate, prepared using the methods described inexample 34 (35 mg, 0.07 mmol) and triethylamine (0.125 mL, 0.9 mmol) inDMF (0.3 mL) was added methylaminoacetonitrile hydrochloride (76 mg, 0.7mmol). The reaction was heated to 90° C. and stirred for 3 h. Aftercooling, and dilution with water and ethyl acetate, the organic waswashed successively with 1 M HCl, brine, dried over magnesium sulfate,filtered and concentrated. HPLC purification (0-90% acetonitrile/water)gave 16 mg (53%) of the title compound as a colorless oil. ¹H NMR(acetone-d₆) δ (ppm) 7.52-7.56 (m, 2H), 7.47 (ddd, 1H, J=8.1, 8.1, 6.0Hz), 7.31-7.42 (m, 4H), 7.10-7.15 (m, 1H), 6.95-6.99 (m, 4H), 5.55 (d,1H, J=4.8 Hz), 4.75 (q, 1H, J=4.4 Hz), 4.10-4.17 (m, 2H). HPLC-MScalculated C₂₂H₁₆Cl₂FNO₃ (M+H⁺): 432.1, found: 432.1.

Example 135N-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)benzenesulfonamide

Sodium hydride (9 mg, 0.21 mmol) was added to a cooled (0° C.) solutionof benzenesulfonamide (34 mg, 0.21 mmol) in DMF (1 mL) under nitrogen.The reaction mixture was stirred for 5 min, at which point the mesylate(from(4S,5R)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one)(72 mg 0.18 mmol) was added and the cooling bath removed, and thereaction was heated to 80° C. with stirring for 4 h. The reactionmixture was cooled and quenched with saturated aqueous solution ofNH₄Cl. Ethyl acetate was added and the organic phase was washed withbrine, dried over magnesium sulfate, filtered and concentrated. HPLCpurification (0-90% acetonitrile/water) gave the title compound (10 mg,12%) as a colorless oil. ¹H NMR (acetone-d₆) δ (ppm) 7.91-7.94 (m, 2H),7.66-7.70 (m, 1H), 7.59-7.63 (m, 2H), 7.47-7.50 (m, 2H), 7.42-7.46 (m,1H), 7.30-7.34 (m, 2H), 7.28 (d, 1H, J=7.8 Hz), 7.24 (ddd, 1H, J=9.7,2.5, 2.5 Hz), 7.19 (t, 1H, J=6.5 Hz), 7.08-7.13 (m, 1H), 5.60 (d, 1H,J=5.8 Hz), 4.49 (ddd, 1H, J=5.7, 4.6, 4.6), 3.46-3.50 (m, 2H). HPLC-MScalculated C₂₂H₁₈ClFN₂O₄S (M+H⁺): 461.1, found: 461.1.

Example 149(S)-3-[4-(6-Chloro-pyridazin-3-yloxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one

Step A: A solution of(S)-3-(4-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one(57 mg, 0.169 mmol, prepared from(S)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and1-iodo-4-methoxy-benzene using the same condition as example 4) inCH₂Cl₂ (1 mL) is cooled down to −78° C. in a dry ice bath when BBr₃(0.371 mmol, 1M in CH₂Cl₂) is added into the mixture dropwise. After theaddition, the mixture is allowed to warm up to 0° C. and stirred for 1h. The reaction is then quenched at 0° C. by adding MeOH (0.5 mL) anddiluted with water (2 mL). After extraction with CH₂Cl₂ (3×2 mL), thecombined organic layers were concentrated and purified by a flash columnchromatography (silica gel, EtOAc/hexane 0-50%) to provide the desired(S)-3-(4-hydroxy-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one(47 mg, 86%). HPLC-MS calculated for C₁₆H₁₂F₃NO₃ (M+H⁺) 324.1, found324.1.

Step B: A mixture of(S)-3-(4-hydroxy-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one(20 mg, 0.062 mmol), 3,6-dichloropyradazine (18.5 mg, 0.124 mmol) andK₂CO₃ (17 mg, 0.124 mmol) in DMF (0.5 mL) is heated to 80° C. for 2 hand then cooled down to room temperature. The mixture is then treatedwith saturated NH₄Cl aqueous solution (4 mL) and extracted with EtOAc(3×2 mL). The combined organic layers were then concentrated andpurified by preparative LC/MS to provide the desired product(S)-3-[4-(6-Chloro-pyridazin-3-yloxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one.¹H NMR (CDCl₃, 400 MHz) δ 7.50˜7.63 (m, 4H), 7.47 (d, 1H), 7.42 (d, 2H),7.09˜7.15 (m, 3H), 5.46 (dd, 1H), 4.82 (t, 1H), 4.19 (dd, 1H); HPLC-MScalculated for C₂₀H₁₃ClF₃N₃O₃ (M+H⁺) 436.1, found 436.1.

Example 151(S)-1-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one

Step A: To a solution of urethane (7.76 g, 87.1 mmol) in n-propanol(˜100 mL) is added freshly prepared NaOH (0.5 M, 174.2 mL, 87.1 mmol).The mixture is stirred at room temperature for 5 min before the additionof 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (8.57 g, 43.5mmol). After the resulted mixture is stirred at room temperature for 10min, a solution of 3-trifluorostyrene (5.00 g, 29.0 mmol) and (DHQ)₂PHAL(564 mg, 0.72 mmol) in n-propanol (70 mL) is added into the solution.Right after the addition, K₂OsO₄.2H₂O (241 mg, 0.72 mmol) in 0.5 M NaOH(2 ml) is added into the mixture and the resulted brownish solution isstirred at room temperature for 14 h. The yellowish reaction mixture isthen diluted with water (200 ml) and poured into a separatory funnel.After extraction with EtOAc (3×200 ml), the combined organic layer iswashed with brine and dried (MgSO₄). After removing the drying agent,the solution is concentrated and purified by flash column chromatography(silica gel, EtOAc/hexane 0%˜65%) to provide the desired(S)-[2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethylester as colorless oil (6.1 g, 75%). ¹H NMR (CDCl₃, 400 MHz) δ 7.58 (s,1H), 7.56 (d, 1H), 7.52 (d, 1), 7.50 (t, 1H), 5.49 (d, 1H), 4.89 (br,1H), 4.12 (m, 2H), 3.94 (br, 1H), 3.86 (br, 1H), 1.98 (br, 1H), 1.25 (t,3H); HPLC-MS calculated for C₁₂H₁₄F₃NO₃ (M+H⁺) 228.1, found 228.1.

Step B: To an ice cooled solution of[2-hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester(6.1 g, 22.0 mmol) in CH₂Cl₂ (50 mL) is added p-toluenesulfonyl chloride(4.40 g, 23.1 mmol) and Et₃N (3.11 g, 30.8 mmol) slowly. After theaddition, the mixture is allowed to warm up to room temperature andstirred for 14 h. The mixture is then poured into water (200 mL) andextracted with CH₂Cl₂ (3×100 ml). The combined organic layer is washedwith brine and dried (MgSO₄). After removing the drying agent, thesolution is concentrated and purified by a wash column (silica gel,0˜45% EtOAc/hexane) to provide the desired product(S)-toluene-4-sulfonic acid2-ethoxycarbonylamino-2-(3-trifluoromethyl-phenyl)-ethyl ester as acolorless oil (7.5 g, 79%). ¹H NMR (CDCl₃, 400 MHz) δ 7.64 (d, 2H), 7.53(m, 1H), 7.43 (m, 3H), 7.27 (d, 2H), 5.40 (br, 1H), 5.03 (m, 1H), 4.31(dd, 1H), 4.21 (dd, 1H), 4.14 (q, 2H), 2.43 (s, 3H), 1.26 (t, 3H);HPLC-MS calculated for C₁₉H₂₀F₃NO₅S (M+H⁺) 432.1, found 432.1.

Step C: To a solution of (S)-toluene-4-sulfonic acid2-ethoxycarbonylamino-2-(3-trifluoromethyl-phenyl)-ethyl ester (7.50 g,17.4 mmol) in DMF (70 mL) is added NaN₃ (1.70 g, 26.1 mmol). Thesuspension is then heated to 70° C. for 2 h. and then cooled down toroom temperature. The majority of the DMF is removed under vacuum andthe resulted residue is treated with water (200 mL) and extracted withEtOAc (3×150 mL). The combined organic layer is washed with brine anddried (MgSO₄). After removing the drying agent, the solution isconcentrated and purified by a wash column (silica gel, EtOAc/hexane0%˜45%) to provide the desired product(S)-[2-Azido-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethylester as colorless oil (4.6 g, 88%). ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (m,2H), 7.52 (m, 2H), 5.29 (br, 1H), 4.98 (m, 1H), 4.13 (m, 2H), 3.73 (q,1H), 3.67 (q, 2H), 1.25 (t, 3H); HPLC-MS calculated for C₁₂H₁₃F₃N₄O₂(M+H⁺) 303.1, found 303.1.

Step D: To a solution of(S)-[2-azido-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethylester (4.60 g, 15.2 mmol) in EtOH (200 mL) is added 10% Pd/C (˜200 mg).The resulted mixture is then degassed and filled with H₂ and stirred atroom temperature under H₂ for 14 h. The mixture is then filtered througha pat of Celite to remove the Pd/C and washed with EtOH (3×10 mL). Thefiltrate is concentrate to provide the crude(S)-[2-amino-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethylester (˜4.0 g, 95%), which is used for next step without furtherpurification.

Crude (S)-[2-amino-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acidethyl ester from above is dissolved in anhydrous EtOH (100 mL).p-Anisaldehyde (2.07 g, 15.2 mmol) is added into the solution andstirred at room temperature for 5 h before the addition of NaBH₄ (0.82g, 21.8 mmol) at 0° C. The mixture is then warmed up to room temperatureand stirred for 14 hr. After the solvent is removed under vacuum, theresidue is treated with saturated NH₄Cl aqueous solution (50 mL) andextracted with EtOAc (3×150 mL). The combined organic layer is washedwith brine and dried (MgSO₄). After removing the drying agent, thesolution is concentrated to provide the crude(S)-[2-(4-methoxy-benzylamino)-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamicacid ethyl ester as colorless oil (˜6.0 g) which is used directly fornext step.

The crude material obtained from above (6.0 g) is dissolved in DMF (75mL) and transferred into a microwave reaction vessel and heated to 220°C. for 15 min in a microwave reactor. The solvent DMF is removed undervacuum and the residue is treated with water (200 mL) and extracted withEtOAc (3×150 mL). The combined organic layer is washed with brine anddried (MgSO₄). After removing the drying agent, the solution isconcentrated and purified by a wash column (silica gel, EtOAc/hexane0%˜85%) to provide the desired product(S)-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-oneas colorless oil (4.7 g, 92%). ¹H NMR (CDCl₃, 400 MHz) δ 7.51 (m, 4H),7.18 (d, 2H), 6.85 (d, 2H), 5.22 (br, 1H), 4.79 (t, 1H), 4.40 (d, 1H),4.27 (d, 1H), 3.79 (s, 3H), 3.68 (t, 1H), 3.05 (dd, 1H); HPLC-MScalculated for C₁₈H₁₇F₃N₂O₂ (M+H⁺) 351.1, found 351.1.

Step E: A mixture of(S)-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one(1.7 g, 4.86 mmol), 4-(4-clorophenoxy)-iodobenzene, (1.77 g, 5.35 mmol),CuI (93 mg, 0.49 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (119mg, 0.97 mmol) and K₃PO₄ (2.06 g, 9.72 mmol) in DMF (17 mL) is degassedand heated to 110° C. under N₂ for 16 h. After cooling down to roomtemperature, the mixture was poured into water (200 mL) and extractedwith EtOAc (3×50 mL). The combined organic layer is washed with brineand dried (MgSO₄). After removing the drying agent, the solution isconcentrated and purified by flash column chromatography (silica gel,EtOAc/hexane 0%˜80%) to provide the desired product(S)-3-[4-(4-chloro-phenoxy)-phenyl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one(example 154) as a white solid (2.1 g, 78%). ¹H NMR (CDCl₃, 400 MHz) δ7.51 (m, 2H), 7.44 (m, 2H), 7.34 (d, 2H), 7.23 (m, 4H), 6.87 (m, 6H),5.17 (dd, 1H), 4.53 (d, 1H), 4.37 (d, 1H), 3.79 (s, 3H), 3.76 (t, 1H),3.07 (dd, 1H); HPLC-MS calculated for C₃₀H₂₄ClF₃N₂O₃ (M+H⁺) 553.1, found553.1.

Step F:(S)-3-[4-(4-chloro-phenoxy)-phenyl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one(2.1 g, 3.8 mmol) is treated with TFA (15 mL) at room temperature for 14h. The excess of TFA is removed under vacuum and the residue is treatedwith saturated NaHCO₃ aqueous solution (50 mL) and extracted with EtOAc(3×100 mL). The combined organic layer is washed with brine and dried(MgSO₄). After removing the drying agent, the solution is concentratedand purified by flash column chromatography (silica gel, EtOAc/hexane0%˜70%) to provide the desired product(S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-oneas white crystals (1.5 g, 91%). ¹H NMR (CDCl₃, 400 MHz) δ 7.45˜7.58 (m,4H), 7.29 (d, 2H), 7.23 (d, 2H), 6.87 (m, 4H), 5.34 (dd, 1H), 4.82 (br,1H), 4.01 (t, 1H), 3.35 (dd, 1H); HPLC-MS calculated for C₂₂H₁₆ClF₃N₂O₂(M+H⁺) 433.1, found 433.1.

Example 153(S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one

Step A: To a solution of 5-bromo-2-fluoro-pyridine (176 mg, 1.00 mmol)in DMF (2 mL) is added 4-chlorophenol (141 mg, 1.1 mmol) and K₂CO₃ (209mg, 1.5 mmol). The resulted mixture is then heated to 85° C. and stirredfor 14 h. the mixture is cooled down to room temperature and treatedwith saturated NH₄Cl aqueous solution (15 mL) and extracted with EtOAc(3×20 mL). The combined organic layer is washed with brine and dried(MgSO₄). After removing the drying agent, the solution is concentratedand purified by flash column chromatography (silica gel, EtOAc/hexane0%˜30%) to provide the desired product5-bromo-2-(4-chloro-phenoxy)-pyridine (220 mg, 78%). HPLC-MS calculatedfor C₁₁H₇BrClNO (M+H⁺) 283.9, found 283.9.

Step B:(S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-oneis prepared from (S)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and5-bromo-2-(4-chloro-phenoxy)-pyridine using the same conditions asexample 4. ¹H NMR (CDCl₃, 400 MHz) δ 8.03 (dd, 1H), 7.88 (d, 1H), 7.62(d, 1H), 7.45˜7.55 (m, 3H), 7.3 (d, 2H), 7.01 (d, 2H), 5.40 (dd, 1H),4.85 (t, 1H), 4.24 (dd, 1H); HPLC-MS calculated for C₂₁H₁₅ClF₃N₃O₂(M+H⁺) 435.1, found 435.1.

Example 155(S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one

Step A: A mixture of 5-amino-2-bromopyrazine (2.0 g, 11.5 mmol),4-chlorophenol (1.61 g, 12.5 mmol), Cs₂CO₃ (5.0 g, 15.4 mmol), CuI (0.21g, 1.1 mmol), N,N-dimethylglycin (0.11 g, 1.1 mmol) in dioxane (22 mL)is degassed and heated to 115° C. under N₂ for 2 h. After cooling downto room temperature, the mixture is diluted with EtOAc (200 mL) andwater (200 mL). The solid is removed by filtration and washed with EtOAc(2×10 mL). The filtrate is put into a separatory funnel for extraction(EtOAc, 3×100 mL). The combined organic layer is washed with brine anddried (MgSO₄). After removing the drying agent, the solution isconcentrated and purified by flash column chromatography (silica gel,EtOAc/hexane 0%˜45%) to provide the desired product5-(4-chloro-phenoxy)-pyrazin-2-ylamine (1.8 g, 74%). HPLC-MS calculatedfor C₁₀H₈ClN₃O (M+H⁺) 222.0, found 222.0.

Step B: To a mixture of 5-(4-chloro-phenoxy)-pyrazin-2-ylamine (1.0 g,4.52 mmol), CuBr (0.65 g, 4.52 mmol) and CuBr₂ (3.03 g, 13.6 mmol) inDMF (20 mL) at 0° C. is added tert-butyl nitrite (1.4 g, 13.6 mmol)dropwise. After the resulted mixture is stirred at room temperature for14 h, it is poured into a 0.05 N HCl aqueous solution (200 mL) andextracted with EtOAc (3×100 mL). The combined organic layer is washedwith brine and dried (MgSO₄). After removing the drying agent, thesolution is concentrated and purified by flash column chromatography(silica gel, EtOAc/hexane 0%˜30%) to provide the desired product2-bromo-5-(4-chloro-phenoxy)-pyrazine as yellowish crystal (1.2 g, 93%).HPLC-MS calculated for C₁₀H₆BrClN₂O (M+H⁺) 284.9, found 284.9.

Step C:(S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-oneis prepared from 4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one and2-bromo-5-(4-chloro-phenoxy)-pyrazine using the same conditions asexample 4. ¹H NMR (CDCl₃, 400 MHz) δ 8.98 (d, 1H), 7.95 (d, 1H),7.47˜7.62 (m, 4H), 7.34 (d, 2H), 7.04 (d, 2H), 5.82 (dd, 1H), 4.88 (t,1H), 4.35 (dd, 1H); HPLC-MS calculated for C₂₀H₁₃ClF₃N₃O₃ (M+H⁺) 436.1,found 436.1.

Example 163(S)-3-[4-(4-Chloro-phenoxy)-phenyl]-1-(2-methanesulfonyl-ethyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one

A solution of(S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one(1.5 g, 3.47 mmol) in anhydrous DMF (20 mL) is cooled down to 0° C. inan ice bath when NaH (194 mg, 60% in mineral oil, 4.86 mmol) is addedinto the solution portion wise. After the addition, the mixture isstirred at 0° C. for 10 min when a solution of vinyl methylsulfone (736mg, 6.94 mmol) in DMF (5 mL) is added into the mixture. The resultedmixture is allowed to warm up to room temperature and stir for 1 h. Themixture is then poured into 10% NH₄Cl aqueous solution (˜300 mL) andextracted with EtOAc (3×100). The combined organic layer is washed withbrine and dried (MgSO₄). After removing the drying agent, the solutionis concentrated and purified by flash column chromatography (silica gel,EtOAc/hexane 0%˜100%) to provide the desired product(S)-3-[4-(4-chloro-phenoxy)-phenyl]-1-(2-methanesulfonyl-ethyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-oneas white solid (1.18 g, 63%) with the recovery of the starting material(S)-1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one(˜300 mg). ¹H NMR (CDCl₃, 400 MHz) δ 7.45˜7.58 (m, 4H), 7.29 (d, 2H),7.23 (d, 2H), 6.87 (m, 4H), 5.27 (dd, 1H), 4.07 (t, 1H), 3.80˜4.10 (m,2H), 3.28˜3.40 (m, 3H), 3.01 (s, 3H); HPLC-MS calculated forC₂₅H₂₂ClF₃N₂O₄S (M+H⁺) 539.1, found 539.1.

Example 164(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethanesulfonamide

Step A: To a solution of 2-chloro-ethanesulfonyl chloride (223 mg, 1.37mmol) in anhydrous CH₂Cl₂ (3 mL) at 0° C. is addedbis-(4-methoxy-benzyl)-amine (370 mg, 1.44 mmol) followed by Et₃N (304mg, 3.01 mmol). After the addition, the mixture is allowed to warm up toroom temperature and stirred for 5 h. The mixture is then poured intowater (5 mL) and extracted with CH₂Cl₂ (3×5 mL). The combined organiclayer is concentrated and purified by flash column chromatography(silica gel, EtOAc/hexane 0%˜30%) to provide the desired productN,N-bis(4-methoxybenzyl)ethenesulfonamide as colorless oil. (300 mg,63%).

Step B:(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)ethanesulfonamideis prepared using the methods described in example 163. HPLC-MScalculated for C₄₀H₃₇ClF₃N₃O₆S (M+H⁺) 780.2, found 780.2.

Step C: A solution of(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)-phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)ethanesulfonamide(2.2 g, 2.82 mmol) in TFA (30 mL) is stirred at room temperature for 14h. Excess of TFA is removed under vacuum. The residue is treated withsaturated NaHCO₃ aqueous solution (30 mL) and extracted with EtOAc (3×50mL). The combined organic layer is washed with brine and dried (MgSO₄).After removing the drying agent, the solution is concentrated andpurified by flash column chromatography (silica gel, EtOAc/hexane0%˜90%) to provide the desired product(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethanesulfonamideas white solid (1.2 g, 83%). ¹H NMR (CDCl₃, 400 MHz) δ 7.55˜7.62 (m,3H), 7.48 (t, 1H), 7.24 (d, 2H), 7.22 (d, 2H), 6.85 (m, 4H), 5.47 (s,2H), 5.28 (dd, 1H), 3.90˜4.03 (m, 3H), 3.40 (dd, 1H), 3.28˜3.35 (m, 2H);HPLC-MS calculated for C₂₄H₂₁ClF₃N₃O₄S (M+H⁺) 540.1, found 540.1.

Example 1652-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)aceticacid

To a solution of ethyl2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetate(12.0 mg, 0.023 mmol) in EtOH (0.5 mL) is added 1N NaOH aqueous solution(115 μL, 0.12 mmol). The mixture is stirred at room temperatureovernight before removal of the solvent. The residue is purified bypreparatory LC/MS to provide the title compound; HPLC-MS calculated forC₂₆H₂₂ClF₃N₂O₄ (M+H⁺) 491.1, found 491.1.

Example 1661-((1H-tetrazol-5-yl)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

To a solution of2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetonitrile(21.8 mg, 0.046 mmol) in DMF (1.0 mL) are added NaN₃ (60 mg, 0.92 mmol)and NH₄Cl (49 mg, 0.92 mmol). The reaction mixture is heated at 220° C.for 15 min in a microwave reactor. After cooling down to roomtemperature and removal of the solvent, the residue is purified bypreparatory LC/MS to provide the title compound; ¹H NMR (CDCl₃, 400 MHz)δ 7.58-7.45 (m, 4H), 7.26 (d, 2H), 7.19 (d, 2H), 6.87 (m, 4H), 5.24 (dd,1H), 4.95 (d, 1H), 4.69 (d, 1H), 4.10 (t, 1H), 3.48 (dd, 1H); HPLC-MScalculated for C₂₄H₁₈ClF₃N₆O₂ (M+H⁺) 515.1, found 515.1.

Example 1672-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-propylacetamide

To a solution of2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)aceticacid (16.0 mg, 0.0326 mmol), HATU (18.6 mg, 0.0489 mmol) and ^(i)Pr₂NEt(17.0 μL, 0.0978 mmol) in DMF (0.5 mL) is added propylamine (5.36 μL,0.0652 mmol). The reaction mixture is stirred at room temperatureovernight before removal of the solvent. The residue is purified bypreparative LC/MS to provide the title compound; HPLC-MS calculated forC₂₇H₂₅ClF₃N₃O₃ (M+H⁺) 532.2, found 532.2.

Example 1692-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetamido)aceticacid

tert-Butyl2-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetamido)acetate(20.0 mg, 0.0332 mmol) is dissolved in a mixture solvent of DCM (0.4 mL)and TFA (0.4 mL). The reaction mixture is stirred at room temperaturefor 3 h before removal of the solvent. The residue is purified byreparative LC/MS to provide the title compound; HPLC-MS calculated forC₂₆H₂₁ClF₃N₃O₅ (M+H⁺) 548.1, found 548.1.

Example 1723-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one

Step A: To a solution of1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one(300 mg, 0.69 mmol) in DMF (3.5 mL) at 0° C. is slowly added NaH (60%dispersion in mineral oil, 33.3 mg, 0.83 mmol). The reaction mixture isstirred at 0° C. for 30 min before 2-(2-bromoethoxy)tetrahydro-2H-pyran(208 μL, 1.38 mmol) is added. The mixture is then stirred at roomtemperature for 2 h before quenched with H₂O (40 mL) and extracted withEtOAc (3×20 mL). The combined organic layer is washed with brine anddried over MgSO₄. After removal of the drying agent and solvent, thecrude3-(4-(4-chlorophenoxy)phenyl)-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-oneis used in next step without further purification.

Step B: The crude product from Step A is dissolved in MeOH (3.5 mL) andp-TSA (6.6 mg, 0.035 mmol) is added. The reaction mixture is stirred atroom temperature for 2 h before removal of the solvent. The residue ispurified by silica gel chromatography (40-90% EtOAc/Hexanes) to providethe title compound (271 mg, 82% in two steps) as a colorless oil-likeproduct; ¹H NMR (CDCl₃, 400 MHz) δ 7.57-7.44 (m, 4H), 7.29 (d, 2H), 7.23(d, 2H), 6.86 (m, 4H), 5.27 (dd, 1H), 4.06 (t, 1H), 3.85 (t, 2H), 3.55(m, 1H), 3.43 (m, 1H), 3.36 (dd, 1H); HPLC-MS calculated forC₂₄H₂₀ClF₃N₂O₃ (M+H⁺) 477.1, found 477.1.

Example 1731-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-imine

Step A: A solution ofN-(2-(4-(4-chlorophenoxy)phenylamino)-2-(3-(trifluoromethyl)phenyl)ethyl)-4-methylbenzenesulfonamide(358 mg, 0.638 mmol) and phenol (180 mg, 1.92 mmol) in 30 wt % HBr inacetic acid (3.5 mL) is heated at 80° C. for 2 h. After cooling down toroom temperature, most of the solvent is removed under vacuo. Theresidue is then quenched with cold saturated NaHCO₃ aqueous solution (40mL) and extracted with EtOAc (3×20 mL). The combined organic layer isconcentrated and purified by reverse phase HPLC to provideN¹-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine(128 mg, 49% yield) as a light yellow oil-like product.

Step B: To a solution ofN¹-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine(20.0 mg, 0.0492 mmol) in EtOH (0.5 mL) are added cyanogen bromide (6.2mg, 0.0590 mmol) and TEA (8.22 μL, 0.0590 mmol). The reaction mixture isheated at 80° C. for 2 h before removal of the solvent. The residue ispurified by preparatory LC/MS to provide the title compound; ¹H NMR(CDCl₃, 400 MHz) δ 7.65-7.50 (m, 4H), 7.33 (d, 2H), 7.01 (d, 2H), 6.94(m, 4H), 5.24 (dd, 1H), 4.30 (t, 1H), 3.79 (dd, 1H); HPLC-MS calculatedfor C₂₂H₁₇ClF₃N₃O (M+H⁺) 432.1, found 432.1.

Example 1741-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidine-2-thione

To a solution ofN¹-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine(127 mg, 0.312 mmol) in EtOH (2.0 mL) are added CS₂ (188 μL, 3.12 mmol)and ^(i)Pr₂NEt (272 μL, 1.56 mmol). The reaction mixture is heated at80° C. overnight before removal of the solvent. The residue is purifiedby silica gel chromatography (0˜40% EtOAc/Hexanes) to provide the titlecompound (95.9 mg, 69% yield) as a white solid product; HPLC-MScalculated for C₂₂H₁₆ClF₃N₂OS (M+H⁺) 449.1, found 449.1.

Example 1752-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylmethanesulfonate

To a solution of3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one(340 mg, 0.713 mmol) in DCM (3.5 mL) at 0° C. are added MsCl (111 μL,1.43 mmol) and TEA (199 μL, 1.43 mmol). The reaction mixture is stirredat room temperature overnight before removal of the solvent. The residueis taken in H₂O (40 mL) and extracted with EtOAc (3×20 mL). The combinedorganic layer is washed with brine, dried over MgSO₄, concentrated, andpurified by silica gel chromatography (20-70% EtOAc/hexanes) to providethe title compound (337 mg, 85% yield) as a colorless oil-like product;HPLC-MS calculated for C₂₅H₂₂ClF₃N₂O₅S (M+H⁺) 555.1, found 555.1.

Example 1761-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-oneoxime

Step A: To a solution of1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidine-2-thione(10.0 mg, 0.0223 mmol) in MeOH (0.5 mL) is added MeI (6.94 μL, 0.111mmol). The reaction mixture is heated at 80° C. for 1 h before removalof the solvent. The crude1-(4-(4-chlorophenoxy)phenyl)-2-(methylthio)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-imidazoleis used in next step without further purification; HPLC-MS calculatedfor C₂₃H₁₈ClF₃N₂OS (M+H⁺) 463.1, found 463.1.

Step B: To a solution of the crude product from previous step in MeOH(0.5 mL) are added NH₂OH.HCl (7.7 mg, 0.111 mmol) and K₂CO₃ (15.4 mg,0.111 mmol). The reaction mixture is heated at 80° C. for 1 h beforeremoval of the solvent. The residue is purified by preparatory TLC toprovide the title compound; HPLC-MS calculated for C₂₂H₁₇ClF₃N₃O₂ (M+H⁺)448.1, found 448.1.

Example 1773-(4-(4-chlorophenoxy)phenyl)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one

A solution of2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethylmethanesulfonate (10.0 mg, 0.0180 mmol) in MeOH (0.3 mL) is heated at60° C. overnight. After removal of the solvent the residue is purifiedby preparatory LC/MS to provide the title compound; ¹H NMR (CDCl₃, 400MHz) δ 7.56-7.44 (m, 4H), 7.30 (d, 2H), 7.23 (d, 2H), 6.86 (m, 4H), 5.22(dd, 1H), 4.07 (t, 1H), 3.57 (m, 3H), 3.49 (m, 1H), 3.36 (dd, 1H), 3.34(s, 3H); HPLC-MS calculated for C₂₅H₂₂ClF₃N₂O₃ (M+H⁺) 491.1, found491.1.

Example 1783-(4-(4-chlorophenoxy)phenyl)-1-(2-(2-hydroxyethylamino)ethyl)-4-(3-(trifluoromethyl)-phenyl)imidazolidin-2-one

To a solution of2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylmethanesulfonate (12.0 mg, 0.0216 mmol) in THF (0.3 mL) is added2-aminoethanol (6.53 μL, 0.108 mmol). The reaction mixture is heated at80° C. for 2 h before removal of the solvent. The residue is purified bypreparatory LC/MS to provide the title compound; HPLC-MS calculated forC₂₆H₂₅ClF₃N₃O₃ (M+H⁺) 520.2, found 520.2.

Example 1812-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylcarbamate

To a solution of3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one(10.0 mg, 0.021 mmol) in DCM (0.3 mL) are added sodium cyanate (5.5 mg,0.084 mmol) and TFA (6.46 μL, 0.084 mmol). The mixture is stirred atroom temperature overnight before removal of the solvent. The residue ispurified by preparatory TLC to provide the title compound; HPLC-MScalculated for C₂₅H₂₁ClF₃N₃O₄ (M+H⁺) 520.1, found 520.1.

Example 1843-(4-(4-chlorophenoxy)phenyl)-1-(2-(piperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one

tert-butyl4-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazo-lidin-1-yl)ethyl)piperazine-1-carboxylate(15 mg, 0.023 mmol) is dissolved in a mixture solvent of DCM (0.2 mL)and TFA (0.2 mL). The reaction mixture is stirred at room temperaturefor 15 min before removal of the solvent. The residue is purified byreparative LC/MS to provide the title compound; HPLC-MS calculated forC₂₈H₂₈ClF₃N₄O₂ (M+H⁺) 545.2, found 545.2.

Example 185 (4R,5S)-methyl1-(4-(4-chlorophenoxy)phenyl)-2-oxo-5-phenylimidazolidine-4-carboxylate

Step A: (2S,3R)-ethyl2-hydroxy-3-(4-methylphenylsulfonamido)-3-phenylpropanoate issynthesized from ethyl cinnamate, using the Sharpless AsymmetricAminohydroxylation (AA) conditions described in Li, G.; Chang, H.-T.;Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 451.

Step B: (2R,3R)-ethyl 3-phenyl-1-tosylaziridine-2-carboxylate issynthesized from (2S,3R)-ethyl2-hydroxy-3-(4-methylphenylsulfonamido)-3-phenylpropanoate, using thecyclodehydration conditions described in Rubin, A. E.; Sharpless, K. B.Angew. Chem. Int. Ed. Engl. 1997, 36, 2637.

Step C and D: (4R,5S)-ethyl1-(4-(4-chlorophenoxy)phenyl)-2-oxo-5-phenyl-3-tosylimidazolidine-4-carboxylateis synthesized from (2R,3R)-ethyl3-phenyl-1-tosylaziridine-2-carboxylate, using the conditions describedin Example 7, Step B and C.

Step E: To a solution of (4R,5S)-ethyl1-(4-(4-chlorophenoxy)phenyl)-2-oxo-5-phenyl-3-tosylimidazolidine-4-carboxylate(15.0 mg, 0.025 mmol) in MeOH (0.5 mL) is added magnesium powder (6.2mg, 0.25 mmol). The reaction mixture is heated in a sealed tube at 80°C. for 1 h. After cooling down to room temperature, the mixture isquenched with saturated NH₄Cl aqueous solution (5 mL) and extracted withEtOAc (3×3 mL). The combined organic layer is concentrated and purifiedby preparatory TLC to provide the title compound; ¹H NMR (CDCl₃, 400MHz) δ 7.39-7.32 (m, 7H), 7.23 (d, 2H), 6.86 (m, 4H), 5.43 (d, 1H), 5.26(br, 1H), 4.08 (d, 1H), 3.87 (s, 3H); HPLC-MS calculated forC₂₃H₁₉ClN₂O₄ (M+H⁺) 423.1, found 423.1.

Example 1903-(4-(4-chlorophenoxy)phenyl)-1-(4-methoxyphenyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one

A reaction tube charged with1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one(20.0 mg, 0.0462 mmol), 4-iodoanisole (13.0 mg, 0.0554 mmol), K₃PO₄(19.6 mg, 0.0924 mmol), and catalytic amount of CuI is purged withnitrogen. 1,4-Dioxane (0.5 mL) and catalytic amount oftrans-1,2-diaminocyclohexane are added via syringe. The reaction mixtureis heated at 100° C. overnight, cooled down to room temperature,quenched with saturated NH₄Cl aqueous solution (5 mL), and extractedwith EtOAc (3×3 mL). The combined organic layer is concentrated andpurified by preparatory LC/MS to provide the title compound; HPLC-MScalculated for C₂₉H₂₂ClF₃N₂O₃ (M+H⁺) 539.1, found 539.1.

Example 1941-(2-aminoethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

2-(3-(4-(4-Chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)ethylmethanesulfonate (85.0 mg, 0.153 mmol) is dissolved in a mixture solventof ^(i)PrOH (0.5 mL) and concentrated ammonia aqueous solution (0.5 mL).The reaction mixture is heated at 80° C. for 2 h, cooled down to roomtemperature, taken in H₂O (10 mL), and extracted with EtOAc (3×5 mL).The combined organic layer is dried over MgSO₄ and evaporated in vacuoto provide the crude title compound (69.7 mg, 96% yield) as a colorlessoil-like product; HPLC-MS calculated for C₂₄H₂₁ClF₃N₃O₂ (M+H⁺) 476.1,found 476.1.

Example 201(S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide

Step A: (R)-Benzyl 2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethylcarbamateis synthesized from 3-(trifluoromethyl)styrene, using the SharplessAsymmetric Aminohydroxylation (AA) conditions described in Li, G.;Angert, H. H.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35,2813, as a white solid product (35% yield); ¹H NMR (CDCl₃, 400 MHz) δ7.57-7.46 (m, 4H), 7.36 (m, 5H), 5.61 (d, 1H), 5.11 (m, 2H), 4.91 (br,1H), 3.94 (dd, 1H), 3.86 (dd, 1H); HPLC-MS calculated for C₁₇H₁₆F₃NO₃(M+H⁺) 340.1, found 340.1.

Step B: To a solution of (R)-Benzyl2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethylcarbamate (4.54 g, 13.4mmol) in MeOH (100 mL) is slowly added 10 wt % Pd/C (454 mg). Thereaction mixture is stirred at room temperature under hydrogen (balloon)for 1.5 h, filtered through celite, and evaporated in vacuo to providecrude (R)-2-amino-2-(3-(trifluoromethyl)phenyl)ethanol (2.70 g, 98%yield) as a white solid product; ¹H NMR (CDCl₃, 400 MHz) δ 7.62 (s, 1H),7.55 (m, 2H), 7.47 (t, 1H), 4.15 (dd, 1H), 3.77 (dd, 1H), 3.57 (dd, 1H);HPLC-MS calculated for C₉H₁₀F₃NO (M+H⁺) 206.1, found 206.1.

Step C: To a solution of the crude product from Step B (1.11 g, 5.45mmol) in 1,2-dichloroethane (25 mL) at 0° C. are added K₂CO₃ (2.26 g,16.4 mmol) and TsCl (2.60 g, 13.6 mmol). The reaction mixture is stirredat room temperature overnight. If reaction is not done at this point,additional K₂CO₃ (0.75 g, 5.45 mmol) and TsCl (1.04 g, 5.45 mmol) areadded and the reaction mixture is stirred for another 24 h. Afterremoval of the solvent, the residue is taken in cold saturated NaHCO₃aqueous solution (100 mL) and extracted with EtOAc (3×50 mL). Thecombined organic layer is washed with brine, dried over MgSO₄,concentrated, and purified by silica gel chromatography (0˜35%EtOAc/Hexanes) to provide(R)-1-tosyl-2-(3-(trifluoromethyl)phenyl)aziridine (1.74 g, 94% yield);¹H NMR (CDCl₃, 400 MHz) δ 7.88 (d, 2H), 7.54 (m, 1H), 7.43 (m, 3H), 7.36(d, 2H), 3.81 (dd, 1H), 3.01 (d, 1H), 2.45 (s, 3H), 2.39 (d, 1H);HPLC-MS calculated for C₁₆H₁₄F₃NO₂S (M+H⁺) 342.1, found 342.1.

Step D: To a solution of the aziridine product from Step C (1.13 g, 3.31mmol) in Et₂O (6.6 mL) are added 4-(4-chlorophenoxy)aniline (0.73 g,3.31 mmol) and LiClO₄ (176 mg, 1.66 mmol). The reaction mixture isstirred at room temperature overnight. After removal of the solvent, thecrude(S)—N-(2-(4-(4-chlorophenoxy)phenylamino)-2-(3-(trifluoromethyl)-phenyl)ethyl)-4-methylbenzenesulfonamideis used in next step without further purification.

Step E: The crude product from Step D is dissolved in DMF (16.5 mL).Cyanogen bromide (1.75 g, 16.6 mmol) and K₂CO₃ (2.29 g, 16.6 mmol) areadded. The reaction mixture is heated at 100° C. for 2 h, cooled down toroom temperature, taken in H₂O (160 mL), and extracted with EtOAc (3×80mL). The combined organic layer is washed with brine, dried over MgSO₄,and evaporated in vacuo.

The residue is then dissolved in 1,4-dioxane (16.5 mL). Cyanogen bromide(1.75 g, 16.6 mmol) and K₂CO₃ (2.29 g, 16.6 mmol) are added. Thereaction mixture is heated at 100° C. for 2 h, cooled down to roomtemperature, taken in H₂O (160 mL), and extracted with EtOAc (3×80 mL).The combined organic layer is washed with brine, dried over MgSO₄,concentrated, and purified by silica gel chromatography (10˜40%EtOAc/Hexanes) to provide the title compound (1.06 g, 52% yield for twosteps) as a light yellow solid product; ¹H NMR (CDCl₃, 400 MHz) δ 7.98(d, 2H), 7.66 (d, 1H), 7.53 (t, 1H), 7.43 (m, 3H), 7.36 (s, 1H), 7.26(d, 2H), 6.91 (m, 4H), 6.85 (d, 2H), 5.00 (dd, 1H), 4.59 (dd, 1H), 4.09(dd, 1H), 2.51 (s, 3H); HPLC-MS calculated for C₃₀H₂₂ClF₃N₄O₃S (M+H⁺)611.1, found 611.1.

Example 203(S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide

To a solution of(S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)-phenyl)imidazolidin-2-ylidene)cyanamide(1.06 g, 1.73 mmol) in MeOH (17 mL) is added magnesium powder (0.42 g,17.3 mmol). The reaction mixture is heated to reflux for 45 min. Aftercooling down to room temperature, the mixture is quenched with saturatedNH₄Cl aqueous solution (150 mL) and extracted with EtOAc (3×75 mL). Thecombined organic layer is washed with brine, dried over MgSO₄,concentrated, and purified by silica gel chromatography (20˜70%EtOAc/Hexanes) to provide the title compound (0.62 g, 78% yield) as awhite solid product; ¹H NMR (CDCl₃, 400 MHz) δ 7.60 (m, 1H), 7.51 (m,3H), 7.27 (d, 2H), 7.15 (d, 2H), 6.88 (m, 4H), 6.65 (br, 1H), 5.40 (dd,1H), 4.21 (t, 1H), 3.63 (dd, 1H); HPLC-MS calculated for C₂₃H₁₆ClF₃N₄O(M+H⁺) 457.1, found 457.1.

Example 208(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(3-(methylsulfonyl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

Step A: To a solution of(S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propylmethanesulfonate (2.22 g, 3.90 mmol) in THF (20 mL) is added NaSCH₃(0.55 g, 7.80 mmol). The reaction mixture is heated to reflux for 2 h,cooled down to room temperature, taken in H₂O (100 mL), and extractedwith EtOAc (3×50 mL). The combined organic layer is washed with brineand dried over MgSO₄. After removal of the drying agent and solvent, thecrude(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(3-(methylthio)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-oneis used in next step without further purification.

Step B: The crude product from Step A is dissolved in DCM (40 mL) andm-CPBA (77%, 2.62 g, 11.7 mmol) is added. The reaction mixture isstirred at room temperature overnight before removal of the solvent. Theresidue is taken in saturated NaHCO₃ aqueous solution (100 mL) andextracted with EtOAc (3×50 mL). The combined organic layer is washedwith brine, dried over MgSO₄, concentrated, and purified by silica gelchromatography (40˜90% EtOAc/hexanes) to provide the title compound(1.47 g, 68% yield for two steps) as a colorless oil-like product; ¹HNMR (CDCl₃, 400 MHz) δ 7.56 (m, 2H), 7.49 (m, 2H), 7.25 (m, 4H), 6.87(m, 4H), 5.27 (dd, 1H), 4.00 (t, 1H), 3.59 (m, 1H), 3.43 (m, 1H), 3.28(dd, 1H), 3.11 (m, 2H), 2.94 (s, 3H), 2.15 (m, 2H); HPLC-MS calculatedfor C₂₆H₂₄ClF₃N₂O₄S (M+H⁺) 553.1, found 553.1.

Example 215 (R)-1-[4-(4-chlorophenoxy)phenyl]-5-phenylpyrrolidin-2-one

Step A (Method 1, Using Standard Buchwald Coupling Conditions): To a 10mL reaction tube fitted with a screw cap is charged with5-phenylpyrrolidin-2-one (26.8 mg, 0.166 mmol),1-(4-iodophenoxy)-4-chlorobenzene (66 mg, 0.199 mmol, 1.2 eq), copperiodide (6.3 mg, 0.033 mmol, 0.2 eq), K₃PO₄ (70.6 mg, 0.333 mmol, 2.0eq), trans-cyclohexane-1,2-diamine (3.8 mg, 0.033 mmol, 0.2 eq) and1,4-dioxane (2 mL). The system is degassed with argon then sealed andheated to 110° C. for 20 h. The reaction is cooled to room temperature,dissolved in ethyl acetate and washed with water and brine. The organicphase is dried over Na₂SO₄, filtered and concentrated in vacuo.Purification on silica gel (0-33% ethyl acetate in hexane) gives1-[4-(4-chlorophenoxy)phenyl]-5-phenylpyrrolidin-2-one as a slightlybrown oil (30.0 mg, 50%).

Step A (Method 2, Using CsF as Base): To a 10 mL reaction tube fittedwith a screw cap is charged with 5-phenylpyrrolidin-2-one (80.5 mg, 0.5mmol), 1-(4-iodophenoxy)-4-chlorobenzene (248 mg, 0.75 mmol, 1.5 eq),copper iodide (5.0 mg, 0.025 mmol, 0.05 eq), CsF (189 mg, 1.25 mmol, 2.5eq), N1,N2-dimethylethane-1,2-diamine (5.5 μL, 0.05 mmol, 0.1 eq) andethyl acetate (1 mL). The system is degassed with argon then sealed andheated to 85° C. for 20 h. The reaction is cooled to room temperature,filtered and concentrated in vacuo. Purification on silica gel (0-33%ethyl acetate in hexane) gives1-[4-(4-chlorophenoxy)phenyl]-5-phenylpyrrolidin-2-one as a colorlessoil (182 mg, 100%).

Step B: The product obtained in step A is then subjected to chiral HPLC,giving (R)-1-[4-(4-chlorophenoxy)phenyl]-5-phenylpyrrolidin-2-one as acolorless oil, along with its (S)-enantiomer. ¹H NMR (CDCl₃) δ (ppm)7.41-7.32 (m, 4H), 7.31-7.23 (m, 5H), 6.92-6.87 (m, 4H), 5.24 (dd,J=7.4, 4.6 Hz, 1H), 2.82-2.78 (m, 1H), 2.71-2.58 (m, 2H), 2.10-2.01 (m,1H). HPLC-MS calculated C₂₂H₁₈ClNO₂ (M+H⁺): 364.11, found: 364.10.

Example 221(R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one

Step A: A 500 mL round-bottomed flask is charged with tert-butylcarbamate (5.42 g, 46.0 mmol) and n-PrOH (48 mL). To this stirredsolution is added freshly prepared aqueous solution of NaOH (1.84 g,46.0 mmol in 75 mL of H₂O), followed by1,3-dichloro-5,5-dimethylhydantoin (4.54 g, 23.0 mmol). After 5 min asolution of (DHQ)₂PHAL (584 mg, 0.75 mmol, 5 mol %) in n-PrOH (42 mL) isadded. 3-Trifluoromethylstyrene (2.58 g, 15.0 mmol, dissolved in 60 mLof n-PrOH) is then added, followed by K₂Os O₂(OH)₄ (221 mg, 0.6 mmol, 4mol %). The resulting solution is stirred at rt for 2 h. The reactionmixture is then cooled in an ice-bath, and the reaction is quenched bythe addition of sodium sulfite (4.41 g, 35.0 mmol) and stirred for 1 h.Evaporation to remove most of n-PrOH, the aqueous solution is extractedwith ethyl acetate (4×100 mL). The combined organic phases were washedwith water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄, andconcentrated and then purified on silica gel (eluent: 0-33% ethylacetate in hexane) to give tert-butyl(S)-1-[3-(trifluoromethyl)phenyl]-2-hydroxyethylcarbamate (2.42 g, 53%)as a colorless oil. HPLC-MS calculated for C₉H₁₁F₃NO (M-Boc+H⁺) 206.07,found 206.10.

Step B: The tert-butyl(S)-1-[3-(trifluoromethyl)phenyl]-2-hydroxyethylcarbamate (4.83 g, 15.8mmol) is dissolved in acetone (120 mL) and added to an aqueous 5% NaHCO₃solution (42 mL). This magnetically stirred heterogeneous mixture iscooled to 0° C. and treated sequentially with KBr (0.192 g, 1.62 mmol)and TEMPO (2.61 g, 16.8 mmol). Sodium hypochloride (4-6%, 39 mL, ca. 20mmol) is then added dropwise over a period of 15 min, while the mixtureis vigorously stirred and maintained at 0° C. After 1 h, additionalsodium hypochloride (7.8 mL, ca. 4 mmol) is added, and stiffing iscontinued at 0° C. for another hour followed by addition of 5% NaHCO₃solution (60 mL). When the acetone is removed on a rotary evaporator,the resulting aqueous layer is washed twice with ether to remove TEMPOimpurities, acidified to pH 6 with 10% citric acid, and extracted withethyl acetate (4×100 mL). The combined organic phases were washed withwater (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄, andconcentrated to give pure acid (4.62 g, 91%) as a colorless oil.

Step C: The N-Boc-protected amino acid obtained in Step B (2.0 g, 6.26mmol) is dissolved with Meldrum's acid (0.97 g, 6.89 mmol) and DMAP(1.23 g, 10.01 mmol) in DCM (30 mL). The reaction mixture is cooled tobelow 0° C. and a solution of DCC (1.56 g, 7.51 mmol) in DCM (15 mL) isadded dropwise over 30 min. The mixture is stirred at 0° C. for 6 h,then it is left at <0° C. overnight. After filtration to removedicyclohexylurea the reaction mixture is washed with 5% KHSO₄ (4×50 mL)and brine (50 mL) and dried in the refrigerator with Na₂SO₄. Filtered,the resulting solution is used for the next step withoutcharacterization or further purification.

Step D: The solution obtained from Step C is cooled to below 0° C. andAcOH (4.13 g, 68.3 mmol) is added. Then NaBH₄ is added in small potionswhile stirring over 30 min. The mixture is stirred at 0° C. for 6 h,then it is left at <0° C. overnight. The reaction mixture is then washedwith brine (3×20 mL) and water (2×20 mL). The organic phase is driedover anhydrous Na₂SO₄, and concentrated to dryness and then purified onsilica gel (0-40% ethyl acetate in hexane) to give tert-butyl(R)-1-[3-(trifluoromethyl)phenyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethylcarbamate(1.76 g, 65% overall yield for two steps) as a white solid. HPLC-MScalculated for C₂₀H₂₄F₃NO₆ (M+Na⁺) 454.16, found 453.80.

Step E: The mixture of tert-butyl(R)-1-[3-(trifluoromethyl)phenyl]-2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethylcarbamate(520 mg, 1.21 mmol) and toluene (15 mL) is stirred at 110° C. for 3 h.Concentration to give(5R)-1-(tert-butoxycarbonyl)-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidine-3-carboxylicacid as a colorless oil. This product is used for the next step withoutfurther purification. HPLC-MS calculated for C₁₂H₁₀F₃NO₃ (M-Boc+H⁺)274.06, found 274.10.

Step F: The mixture of(5R)-1-(tert-butoxycarbonyl)-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidine-3-carboxylicacid obtained in Step E (ca. 1.21 mmol) and 30% TFA in DCM (6 mL) isstirred at rt for 30 min The reaction mixture is then dissolved in DCM(120 mL), washed with saturated aq. NaHCO₃ (40 mL) and brine (40 mL) anddried over Na₂SO₄. Concentration to give(R)-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one as a slight brownsolid (278 mg, 100% overall yield for two steps). This product is usedfor the next step without further purification. HPLC-MS calculated forC₁₁H₁₀F₃NO (M+H⁺) 230.07, found 230.00.

Step G: To a 10 mL reaction tube fitted with a screw cap is charged with(R)-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (90 mg, 0.39 mmol) and1,4-dioxane (3 mL). 1-(4-iodophenoxy)-4-chlorobenzene (157 mg, 0.47mmol) is then added, followed by copper iodide (15 mg, 0.078 mmol),N,N′-1,2-trans-dimethylcyclohexane-1,2-diamine (11.2 mg, 0.078 mmol),and K₃PO₄ (167 mg, 0.78 mmol). The system is degassed with argon thensealed and heated to 110° C. for 28 h. The reaction is cooled to roomtemperature, dissolved in ethyl acetate and washed with water and brine.The organic phase is dried over Na₂SO₄, filtered and concentrated invacuo. Purification on silica gel (0-30% ethyl acetate in hexane) gave(R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-oneas a slightly yellow oil (102 mg, 60%). ¹H NMR (CDCl₃) δ (ppm) 7.60-7.50(m, 1H), 7.49-7.37 (m, 3H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 2H),6.91-6.67 (m, 4H), 5.28 (dd, J=6.8, 5.6 Hz, 1H), 2.84-2.59 (m, 3H),2.07-1.94 (m, 1H). HPLC-MS calculated for C₂₃H₁₇ClF₃NO₂ (M+H⁺) 432.09,found 432.10.

Example 222(R)-1-[4-(4-chlorophenoxy)phenyl]-2-[3-(trifluoromethyl)phenyl]pyrrolidine

A mixture of(R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one(6.4 mg, 0.015 mmol), THF (0.5 mL) and 9-BBN (0.5 M in hexane, 0.5 mL)is stirred at room temperature overnight. After concentration, theresidue is purified on silica gel (0-30% ethyl acetate in hexane) togive the title compound (5.1 mg, 82%) as a colorless oil. HPLC-MScalculated for C₂₃H₁₉ClF₃NO (M+H⁺) 418.11, found 418.10.

Example 228(R)-5-[3-(2-hydroxyethoxy)phenyl]-1-[5-(4-chlorophenoxy)pyrazin-2-yl]pyrrolidin-2-one

Step A: A screw-capped tube equipped with a magnetic stir bar is chargedwith m-anisaldehyde (3.04 mL, 25 mmol), methyl acrylate (4.50 mL, 50mmol), (PPh₃)₃RhCl (1.16 g, 1.25 mmol), 2-amino-3-picoline (1.06 mL, 10mmol), and benzoic acid (702 mg, 5 mmol). The reaction mixture isstirred at 130° C. for 3 days. After cooling to room temperature, theresulting mixture is dissolved in diethyl ether and ished with water andbrine. The organic phase is then dried over Na₂SO₄ and concentrated. Theresidue is then purified on silica gel (10-30% ethyl acetate in hexane)to give methyl 4-(3-methoxyphenyl)-4-oxobutanoate (5.02 g, 90%) as aclear reddish brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.57 (d, J=9.5 Hz,1H), 7.51 (dd, J=3.0, 2.0 Hz, 1H), 7.38 (t, J=10.0 Hz, 1H), 7.12 (ddd,J=10.5, 3.5, 1.0 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 3.32 (t, J=8.5 Hz,2H), 2.77 (t, J=8.5 Hz, 2H).

Step B: A dried, 25 mL round-bottom flask equipped magnetic stirring baris cooled to room temperature under a stream of nitrogen. To this isadded (−)-DIP-Chloride (6.76 mmol, 2.17 g, 1.2 eq) and THF (10 mL), andthe mixture is cooled to −25° C., followed by the addition of methyl4-(3-methoxyphenyl)-4-oxobutanoate (5.63 mmol). The resulting mixture isthen stirred at −20° C. to −30° C. for 10 h. Then, diethanolamine (12.39mmol, 2.2 eq) is added at −20° C., and the mixture is warmed to roomtemperature and stirred overnight. This mixture is then filtered,evaporated, and the residue is purified on silica gel (0-33% ethylacetate in hexane) to give (S)-methyl4-hydroxy-4-(3-methoxyphenyl)butanoate (985 mg, 79%; >95% based onrecovered starting material) as a clear colorless oil. ¹H NMR (CDCl₃) δ7.33-7.27 (m, 1H), 6.92-6.84 (m, 3H), 5.52-5.46 (m, 1H), 3.82 (s, 1H),3.48 (s, 1H), 2.71-2.61 (m, 3H), 2.26-2.12 (m, 1H).

Step C: The (S)-methyl 4-hydroxy-4-(3-methoxyphenyl)butanoate (985 mg)is dissolved in CH₂Cl₂ (10 mL), and the solution is cooled to 0° C.Trifluoroacetic acid (˜4 drops) is added and the mixture is stirred for8 h at room temperature to complete the lactonization. The reaction isquenched with aqueous sodium bicarbonate, and the organic layer iswashed with water, dried (Na₂SO₄), and concentrated to yield 827 mg(100%) of (S)-dihydro-5-(3-methoxyphenyl)furan-2(3H)-one as a colorlessoil.

Step D: To a stirred solution of 5-(4-chlorophenoxy)pyrazin-2-amine (149mg, 0.67 mmol) in dry CH₂Cl₂ (1.5 mL) at room temperature, under argon,is added trimethylaluminum (0.335 mL of a 2.0 N solution in toluene,0.67 mmol) dropwise. The resulting mixture is stirred for 15 min, then(S)-dihydro-5-(3-methoxyphenyl)furan-2(3H)-one (107 mg, 0.555 mmol) inCH₂Cl₂ (1.5 mL) is added slowly and stirring is continued at ambienttemperature for 3 days. The reaction is quenched carefully with 10%aqueous citric acid (0.5 mL) at 0° C. The mixture is then partitionedbetween saturated aqueous NaHCO₃ (10 mL) and CH₂Cl₂ (10 mL). The aqueouslayer is extracted further with CH₂Cl₂ (3×10 mL). The combined organicextracts are dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue is then purified on silica gel (0-75% ethyl acetate in hexane)to give(S)—N-[5-(4-chlorophenoxy)pyrazin-2-yl]-4-hydroxy-4-(3-methoxyphenyl)butanamide(230 mg, 100%) as a white solid.

Step E: Tri-n-butylphosphine (0.178 mL, 0.72 mmol) is added to asolution of di-tert-butyl azodicarboxylate (167 mg, 0.72 mmol) in dryTHF (1.5 mL) at room temperature. The resulting mixture is stirred for 5min at room temperature, then added dropwise to a solution of(S)—N-[5-(4-chlorophenoxy)pyrazin-2-yl]-4-hydroxy-4-(3-methoxyphenyl)butanamide (194 mg, 0.47 mmol) in THF (1.5 mL) at 0° C. and under argon.The reaction mixture is allowed to warm slowly to ambient temperatureand stirred for 1.5 h, then partitioned between saturated aqueous NaHCO₃(5 mL) and CH₂Cl₂ (10 mL). The aqueous layer is extracted with CH₂Cl₂(3×10 mL). The combined organic extracts are dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue is then purified onsilica gel (0-33% ethyl acetate in hexane) to give(R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-methoxyphenyl)pyrrolidin-2-one(130 mg, 70%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 9.11 (d,J=1.2 Hz), 7.99 (d, J=1.6 Hz, 1H), 7.37-7.31 (m, 1H), 7.22 (t, J=8.0 Hz,1H), 7.07-7.02 (m, 2H), 6.81-6.72 (m, 3H), 5.68 (dd, J=8.2, 3.8 Hz, 1H),3.77 (s, 3H), 2.89-2.74 (m, 1H), 2.72-2.57 (m, 2H), 2.10-1.99 (m, 1H).HPLC-MS calculated C₂₁H₁₈ClN₃O₃ (M+H⁺): 396.11, found: 396.10.

Step F: A mixture of(R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-methoxyphenyl)pyrrolidin-2-one(286 mg, 0.72 mmol), DCM (10 mL) and BBr₃ (1M in DCM, 4 mL) is stirredat room temperature for 1 h. The reaction mixture is then diluted withDCM (120 mL), washed with saturated NaHCO₃ (20 mL) and brine (20 mL) anddried over Na₂SO₄. After concentrating, the residue is purified onsilica gel (0-33% ethyl acetate in hexane) to give(R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-hydroxyphenyl)pyrrolidin-2-one(276 mg, 100%) as a white solid. HPLC-MS calculated for C₂₀H₁₆ClN₃O₃(M+H⁺) 382.09, found 382.10.

Step G: A mixture of(R)-1-[5-(4-chlorophenoxy)pyrazin-2-yl]-5-(3-hydroxyphenyl)pyrrolidin-2-one(276 mg, 0.72 mmol), acetone (9 mL), K₂CO₃ (996 mg, 7.2 mmol) and2-iodoethanol (1.86 g, 10.8 mmol) is stirred at 70° C. for 65 h. Then,acetone is removed by evaporation and the residue is dissolved in ethylacetate (120 mL), washed with brine (20 mL) and dried over Na₂SO₄. Afterconcentration, the residue is purified on silica gel (0-50% ethylacetate in hexane) to give the title compound (215 mg, 70%) as acolorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 9.12 (s, 1H), 7.99 (s, 1H),7.37-7.32 (m, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.08-7.03 (m, 2H), 6.84-6.74(m, 3H), 5.68 (dd, J=8.0, 3.2 Hz, 1H), 4.09-3.99 (m, 2H), 3.98-3.92 (m,2H), 2.89-2.75 (m, 1H), 2.72-2.58 (m, 2H), 2.09-1.98 (m, 1H). HPLC-MScalculated for C₂₂H₂₀ClN₃O₄ (M+H⁺) 426.12, found 426.10.

Example 243 and Example 244(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-[2-(methylsulfonyl)ethyl]pyrrolidin-2-one&(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-[2-(methylsulfonyl)ethyl]pyrrolidin-2-one

Step A: A solution of(R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one(67 mg, 0.155 mmol) in THF (1 mL) is cooled to 0° C., then LiHMDS (0.31mL, 1.0 M in THF, 0.31 mmol) is added. After addition, the resultingsolution is further stirred at 0° C. for 45 min. Then allyl iodide (52mg, 0.31 mmol) is added at 0° C. The resulting mixture is stirred at 0°C. for 1 h and 45 min, then the reaction is quenched with saturatedNH₄Cl solution (0.2 mL). THF is removed by evaporation and then theresidue is dissolved in CH₂Cl₂ (40 mL), washed with brine (10 mL) anddried over Na₂SO₄. After concentration, the residue is purified onsilica gel (0-50% ethyl acetate in hexane) to give(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one(58.5 mg, 80%) and its (3R)-diastereomer (6.5 mg, 9%) as a colorlessoil. HPLC-MS calculated for C₂₆H₂₁ClF₃NO₂ (M+H⁺) 472.12, found 472.10.

Step B:(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one(56 mg, 0.119 mmol) is dissolved in 3 mL of a 2:1 mixture of CH₂Cl₂-MeOHand is cooled to −78° C. Ozone is bubbled through the solution until ablue color persisted and then nitrogen is bubbled through until it isclear. NaBH₄ (2.5 eq) is added and the reaction mixture is allowed towarm to room temperature. The mixture is stirred for 2 h, and then mostof the solvent is removed by evaporation in vacuo. Water is added (10mL) and the aqueous layer is extracted with ethyl acetate (5×10 mL). Thecombined extracts are washed with brine (10 mL), dried over Na₂SO₄,filtered and evaporated. The residue is purified on silica gel (0-55%ethyl acetate in hexane) to give(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(2-hydroxyethyl)pyrrolidin-2-one(51 mg, 89%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.51-7.46 (m,1H), 7.44-7.37 (m, 2H), 7.36-7.30 (m, 3H), 7.21-7.16 (m, 2H), 6.87-6.78(m, 4H), 5.21 (dd, J=10.5, 2.0 Hz, 1H), 3.85-3.68 (m, 2H), 2.97-2.85 (m,1H), 2.45-2.32 (m, 1H), 2.26-2.15 (m, 2H), 2.10-1.98 (m, 1H), 1.80-1.69(m, 1H). HPLC-MS calculated for C₂₅H₂₁ClF₃NO₃ (M+H⁺) 476.12, found476.10.

Step C: To a solution of(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(2-hydroxyethyl)pyrrolidin-2-one(50 mg, 0.105 mmol) in DCM (2 mL) at 0° C. is added MsCl (26 μL) and TEA(50 μL). The reaction mixture is stirred at room temperature for 45 minbefore removal of the solvent. The residue is purified on silica gel(0-50% ethyl acetate in hexane) to give2-{(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}ethylmethanesulfonate (54.3 mg, 93%) as a colorless oil.

Step D: To a solution of2-{(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}ethylmethanesulfonate (54.3 mg, 0.098 mmol) in THF (2 mL) is added NaSMe(excess). The reaction mixture is stirred at room temperature for 64 hbefore removal of the solvent. The crude(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-[2-(methylthio)ethyl]pyrrolidin-2-oneis used in next step without further purification.

Step E: The crude product from Step D is dissolved in CH₂Cl₂ (3 mL) andm-CPBA (77%, excess) is added at 0° C. The reaction mixture is stirredat room temperature overnight before removal of the solvent. The residueis dissolved in CH₂Cl₂ (60 mL) and washed with saturated NaHCO₃ aqueoussolution (10 mL) and brine (10 mL). The organic layer is dried overNa₂SO₄, concentrated, and purified on silica gel (0-75% ethyl acetate inhexane) to give as(3R,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-[2-(methylsulfonyl)ethyl]pyrrolidin-2-oneas a colorless oil (33 mg, 63% for two steps) ¹H NMR (CDCl₃, 400 MHz) δ7.58-7.53 (m, 1H), 7.51-7.44 (m, 2H), 7.41-7.36 (m, 3H), 7.28-7.23 (m,2H), 6.93-6.85 (m, 4H), 5.27 (dd, J=10.5, 2.5 Hz, 1H), 3.48 (ddd,J=17.5, 13.5, 7.0 Hz, 1H), 3.21 (ddd, J=17.5, 13.0, 6.5 Hz, 1H),3.00-2.88 (m, 1H), 2.95 (s, 3H), 2.53-2.37 (m, 1H), 2.37-2.24 (m, 2H),2.23-2.12 (m, 1H). HPLC-MS calculated for C₂₆H₂₃ClF₃NO₄S (M+H⁺) 538.10,found 538.10; and(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-[2-(methyl-sulfonyl)ethyl]pyrrolidin-2-oneas a colorless oil (15 mg, 28% for two steps) ¹H NMR (CDCl₃, 400 MHz) δ7.52-7.47 (m, 1H), 7.45-7.34 (m, 3H), 7.27-7.21 (m, 2H), 7.21-7.16 (m,2H), 6.89-6.81 (m, 4H), 5.21 (dd, J=11.5, 8.0 Hz, 1H), 3.52 (ddd,J=17.5, 12.5, 7.0 Hz, 1H), 3.29 (ddd, J=17.5, 12.0, 7.0 Hz, 1H), 2.97(s, 3H), 2.96-2.84 (m, 2H), 2.46-2.34 (m, 1H), 2.26-2.12 (m, 1H),1.76-1.65 (m, 1H). HPLC-MS calculated for C₂₆H₂₃ClF₃NO₄S (M+H⁺) 538.10,found 538.10.

Example 254(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-[3-(methylsulfonyl)propyl]pyrrolidin-2-one

Step A: To a solution of(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one(61.5 mg, 0.13 mmol) in dry THF (1 mL) at 0° C. and argon is addeddropwise a 9-BBN solution (0.57 mL, 0.5 M in hexane). After the additionis complete, the reaction mixture is stirred at 0° C. for 2 h and atroom temperature for 3 h. The mixture is then cooled to 0° C. andtreated with a 3M NaOH (0.3 mL). The oxidation is carried out by slowaddition of 35% H₂O₂ (0.3 mL) at 0° C. The reaction mixture is stirredat 0° C. for 1 h and then at room temperature overnight. The resultingsolution is poured into ethyl acetate (50 mL), washed with brine (10mL), dried over Na₂SO₄, filtered and evaporated. The residue is purifiedon silica gel (0-50% ethyl acetate in hexane) to give(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(3-hydroxypropyl)pyrrolidin-2-one(64 mg, 100%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.60-7.51(m, 1H), 7.50-7.43 (m, 2H), 7.43-7.35 (m, 3H), 7.28-7.22 (m, 2H),6.93-6.83 (m, 4H), 5.24 (dd, J=10.5, 3.0 Hz, 1H), 3.70 (t, J=7.2 Hz,2H), 2.87-2.75 (m, 1H), 2.45-2.33 (m, 1H), 2.26-2.16 (m, 1H), 2.11-1.98(m, 1H), 1.87 (s, br, 1H), 1.75-1.58 (m, 3H). HPLC-MS calculated forC₂₆H₂₃ClF₃NO₃ (M+H⁺) 490.13, found 490.10.

Step B: To a solution of(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(3-hydroxypropyl)pyrrolidin-2-one(34 mg, 0.070 mmol) in DCM (3 mL) at 0° C. is added MsCl (50 μL) and TEA(100 μL). The reaction mixture is stirred at room temperature overnightbefore removal of the solvent. The residue is purified on silica gel(0-50% ethyl acetate in hexane) to give3-{(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}propylmethanesulfonate (39.1 mg, 99%) as a colorless oil.

Step C: To a solution of3-{(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}propylmethanesulfonate (39.1 mg, 0.069 mmol) in THF (1 mL) is added NaSMe(excess). The reaction mixture is stirred at room temperature for 16 hbefore removal of the solvent. The crude product is then dissolved inCH₂Cl₂ (1 mL) and m-CPBA (77%, excess) is added at 0° C. The reactionmixture is stirred at room temperature for 1 h before removal of thesolvent. The residue is dissolved in CH₂Cl₂ (60 mL) and washed withsaturated NaHCO₃ aqueous solution (10 mL) and brine (10 mL). The organiclayer is dried over Na₂SO₄, concentrated, and purified on a silica gel(0-75% ethyl acetate in hexane) to give the title compound as acolorless oil (33.1 mg, 87%). ¹H NMR (CDCl₃, 400 MHz) δ 7.57-7.53 (m,1H), 7.51-7.44 (m, 2H), 7.43-7.36 (m, 3H), 7.28-7.22 (m, 2H), 6.93-6.85(m, 4H), 5.25 (dd, J=10.5, 2.5 Hz, 1H), 3.12-3.03 (m, 2H), 2.92 (s, 3H),2.85-2.74 (m, 1H), 2.46-2.34 (m, 1H), 2.24 (ddd, J=16.0, 10.0, 3.0 Hz,1H), 2.16-1.94 (m, 3H), 1.79-1.67 (m, 1H). HPLC-MS calculated forC₂₇H₂₅ClF₃NO₄S (M+H⁺) 552.11, found 552.10.

Example 269(S)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)oxazolidin-2-one

Reference: Org Lett 2003, 5(21), 3799. A small reaction tube fitted witha screw cap containing a septum is charged with(S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-oxazolidin-2-one (0.06 mmol),2-bromopyrazine (0.076 mmol), CuI (0.04 mmol), N,N-dimethylglycine (0.04mmol), Cs₂CO₃ (0.13 mmol) and 1,4-dioxane (1 mL) is stirred at 120° C.for 18 h. The reaction mixture is then cooled to room temperature andfiltered through a Whatman 0.42 μM filter and purified by preparativeHPLC (C-18, 10-90% ACN/water (0.05% TFA)). ¹H NMR (CDCl₃, 400 MHz) δ8.41 (d, J=1.2 Hz, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.04 (dd, J=2.8, 1.2 Hz,1H), 7.43 (t, J=8.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.2 Hz,2H), 7.12-7.19 (m, 2H), 7.10 (s, 1H), 5.37 (dd, J=8.8, 6.0 Hz, 1H), 4.80(t, J=8.8 Hz, 1H), 4.26 (dd, J=8.8, 6.0 Hz, 1H); HPLC-MS calculated forC₁₉H₁₄ClN₃O₃ (M+H⁺) 368.1, found 368.1.

The above procedure is also applied towards the preparation of Example278, Example 292, Example 297, Examples 300-303, and Examples 305-306.See Table for spectral data.

Example 270 (S)-methyl5-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-dioxide-2-carboxylate

Step 1: To a dry round bottom flask is added[2-hydroxy-1-(3-methoxy-phenyl)ethyl]-carbamic acid benzyl ester (300mg, 1 mmol), 1-(4-chlorophenoxy)-4-iodobenzene (330 mg, 1 mmol), K₃PO₄(210 mg), 1,2-cyclohexanediamine (15 μL) and CuI (20 mg), and DMF (5mL). The mixture is evacuated and back-filled with nitrogen three times.The reaction mixture is heated to 110° C. for 7 h. The reaction is thencooled to room temperature, diluted with EtOAc (50 mL), washed with 1NHCl, and brine, subsequently dried over MgSO₄, filtered, andconcentrated to give the crude product, which is purified by flashchromatography on silica gel (EtOAc/Hex: 1/2) to provide3-[4-(4-chlorophenoxy)phenyl]-4-(3-methoxyphenyl)-oxazolidin-2-one (304mg).

Step 2: A solution of the product from step 1 (293 mg) in 3 mL ofNaOH/MeOH (10%, w/w) is heated to 60° C. for 6 h, then subsequentlycooled to room temperature and concentrated. The residue is dissolved inEtOAc (30 ml) and is washed with brine, and dried over MgSO₄, filtered,and concentrated to give the crude product, which is by purified flashchromatography on silica gel (EtOAc/Hex: 1/1) to provide2-[4-(4-chloro-phenoxy)-phenylamino]-2-(3-methoxy-phenyl)-ethanol (202mg).

Step 3: A solution of the Step 2 product (185 mg) in 10 ml THF istreated with Burgess' reagent (310 mg, 2.5 eq) in 3 mL THF. The reactionmixture is heated to reflux for 8 h, then cooled to room temperature.DCM (30 mL) is added to the mixture which is then washed with 1N HCl,brine, then dried over MgSO₄, filtered, concentrated, and purified byflash chromatography on silica gel (EtOAc/Hex: 1/1) to afford 208 mg ofthe title compound. ¹H NMR (CDCl₃, 400 MHz) δ 7.27-7.31 (4H, m), 7.22(1H, t, J=8.0 Hz), 6.87-6.93 (6H, m), 6.81 (1H, dd, J=2.8, 0.8 Hz), 5.05(1H, dd, J=9.6, 6.4 Hz), 4.25 (1H, dd, J=6.0, 1.6 Hz), 3.95 (3H, s),3.81 (1H, t, J=6.0 Hz), 3.72 (3H, s); HPLC-MS calculated forC₂₃H₂₁ClN₂O₆S (M+H⁺): 489.1, found 489.1.

See reference: K. C. Nicolaou et al Angew. Chem. Int. Ed. 2002, 41,3806.

Example 271(S)-2-(4-(4-chlorophenoxy)phenyl)-3-(3-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-dioxide

A solution of (S)-methyl5-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-dioxide-2-carboxylate(24 mg) in MeOH/20% NaOH—H₂O/THF (2/1/1) is stirred at room temperaturefor 1 h. The reaction mixture is neutralized with 1N HCl and extractedwith EtOAc (3×10 mL). The combined extracts are washed with brine anddried. Concentration and purification of the residue by flashchromatography (EtOAc/Hex: 1:1) afford 17 mg of the title compound. ¹HNMR (CDCl₃) δ 7.23-7.30 (3H, m), 7.18-7.21 (2H, d, J=6.8 Hz), 6.97 (1H,br s), 6.85-6.92 (5H, m), 6.83 (1H, dd, J=2.4, 0.8 Hz), 5.13 (1H, t,J=6.4 Hz), 4.69 (1H, J=8.0 Hz), 3.98 (1H, m), 3.78 (3H, s), 3.45 (1H,m); HPLC-MS calculated for C₂₁H₁₉ClN₂O₄S (M+H⁺): 431.1, found 431.1

General Procedure I

General Method for O-Arylation of(S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one with BoronicAcids. Reference to O-Arylation with Boronic Acids: Tetrahedron Lett.1998, 39, 2933-2936. To a septum cap tube is combined 4 Å powdermolecular sieves, phenol (0.10 mmol, 1 equiv.), phenyl boronic acid (2equiv.), Cu(OAc)₂ (2 equiv.), triethylamine or pyridine (5 equiv.) inanhydrous acetonitrile or dichloromethane (1 mL). The mixture is stirredat room temperature for 18-42 h. The mixture is then filtered through aWhatman 0.42 μM filter and purified by preparatory LC-MS purification(C-18, 10-90% ACN/water (0.05 TFA)) to give the title compound.

Example 272(S)-4-(3-(m-tolyloxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one

The title compound is prepared by the general O-arylation procedure with3-methylphenylboronic acid to give the title compound. HPLC-MScalculated for C₂₂H₁₈ClNO₃ (M+H⁺): 380.1, found 380.1.

The above O-arylation procedure is applied towards the preparation ofExample 273, Example 274, Example 275, and Example 304. See Table forspectral data.

Example 276(S)-4-(3-(2-cyanophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one

To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.07mmol) is added K₂CO₃ (0.14 mmol) and 2-fluorobenzonitrile (0.08 mmol) inDMSO (1 mL). The mixture is degassed with N₂ (2×) and stirred at 80° C.for 2-3 hours. The mixture is filtered through a Whatman 0.42 μM filterand purified by preparatory LC-MS (C-18, 10-90% ACN/water (0.05% TFA)).HPLC-MS calculated for C₂₂H₁₅ClN₂O₃ (M+H⁺): 391.1, found 391.0.

Example 279(S)-3-(4-chlorophenyl)-4-(3-(pyrimidin-2-yloxy)phenyl)oxazolidin-2-one

To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.05mmol) is added Cs₂CO₃ (0.1 mmol) and 2-chloropyrimidine (0.06 mmol) inDMF (1 mL). The mixture is stirred at 80° C. for 3 h then cooled to roomtemperature and filtered through Whatman 0.42 μM filter and purified bypreparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MScalculated for C₁₉H₁₄ClN₃O₃ (M+H⁺): 368.0, found 368.0.

The same procedure is applied towards the preparation of Example 299.See Table for spectral data.

Example 280 (S)-3-(4-chlorophenyl)-4-(3-ethoxyphenyl)oxazolidin-2-one

To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.07mmol), K₂CO₃ (0.37 mmol) in DMF (0.5 mL) is added iodoethane (0.14 mmol)and the reaction stirred at 60° C. overnight, then cooled to roomtemperature, filtered through a Whatman 0.42 μM filter and purified bypreparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MScalculated for C₁₇H₁₆ClNO₃ (M+H⁺): 318.1, found 318.0.

This procedure is applied towards the preparation of Example 281(LDN547), Example 282 (LDN548), Example 283, Example 284, and Example285. See Table for structures and spectral data.

Example 2881-(4-(4-chlorophenoxy)phenyl)-5-(3-(benzyloxy)phenyl)imidazolidin-2-one

Step 1: Reference to α-amino nitrile synthesis: Synlett, 2005, 8, 1325.A methanol solution (50 mL) of 3-benzyloxybenzaldehyde (5 g, 23.6 mmol),4-amino-4-chlorodiphenyl ether (5.7 g, 25.9 mmol), iodine (120 mg, 0.47mmol) and trimethylsilylcyanide (3.8 mL, 28.3 mmol) is stirred at roomtemperature for 18 h. The precipitate that formed is collected andrinsed with ethyl acetate/hexane (1:4) to obtain ˜7 g (67%) of2-(4-(4-chlorophenoxy)phenylamino)-2-(3-(benzyloxy)phenyl)acetonitrileas a light brown solid.

Step 2: A suspension of the α-amino nitrile (3 g, 6.8 mmol) from Step 1in ether is cooled to −78° C. and is treated with lithium aluminumhydride (1.0 M solution in ether, 27.2 mmol) via slow addition. Thecooling bath is removed and the reaction is allowed to warm to roomtemperature. Upon completion, 500 μL of water is added at 0° C. and themixture stirred for 15 min. The mixture is filtered through a bed ofCelite and the filtrate concentrated and purified by silica gelchromatography (eluting with 7N NH₃ in IPA/methanol/dichloromethane0.1:1:9) to give 1.5 g of4-(4-chlorophenoxy)-N-(2-amino-1-(3-(benzyloxy)phenyl)ethyl)benzenamineas an oily brownish foam (50%).

Step 3: To the diamine (440 mg, 0.98 mmol) from Step 2, andtriethylamine (330 μL, 2.4 mmol) in THF (20 mL) is added triphosgene(180 mg, 0.6 mmol) in THF at 0° C. After complete addition, the mixtureis quenched with water and THF is removed by evaporation. The residue isextracted with ethyl acetate and washed with water. Evaporation of theorganics gives a solid which is triturated with ethyl acetate, filtered,and washed with 40% ethyl acetate/hexane to give 279 mg of the titlecompound. Purification of the filtrate gives an additional 127 mg ofproduct (combined yield, 88%). HPLC-MS calculated for C₂₈H₂₃ClN₂O₃(M+H⁺): 471.1, found 471.1.

Example 2893-(4-(4-chlorophenoxy)phenyl)-4-(3-(benzyloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one

To1-(4-(4-chlorophenoxy)phenyl)-5-(3-(benzyloxy)phenyl)imidazolidin-2-one(Example 288) (200 mg, 0.42 mmol) in 5 mL DMF is added sodium hydride(19 mg, 0.47 mmol) followed by methyl vinyl sulfone (41 μL, 0.47 mmol).After 30 minute, the reaction is cooled to 0° C. and sat. ammoniumchloride is added slowly to the reaction mixture. The reaction mixtureis extracted with ethyl acetate (2×) and purified by flashchromatography gives 171 mg (71%) of the title compound. HPLC-MScalculated for C₃₁H₂₉ClN₂O₅S (M+H⁺): 577.2, found 577.2.

Example 2903-(4-(4-chlorophenoxy)phenyl)-4-(3-hydroxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one

To3-(4-(4-chlorophenoxy)phenyl)-4-(3-(benzyloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one(Example 289) (200 mg, 0.35 mmol) in methanol/ethyl acetate (1:3) isadded 20 mg Pd/C. The mixture is stirred under H₂ atmosphere for 30minutes. Filtration through a bed of celite and evaporation yields 178mg of the title compound as a white solid. ¹H NMR (CDCl₃) δ 7.32-7.29(m, 2H), 7.25-7.19 (m, 2H), 7.19-7.15 (m, 1H), 6.88-6.83 (m, 4H),6.79-6.73 (m, 3H), 5.10 (dd, J=9.2, 5.6 Hz, 1H), 3.97-3.88 (m, 2H),3.75-3.68 (m, 1H), 3.38 (dd, J=8.8, 6.0 Hz, 1H), 3.36 (t, J=6.4 Hz, 2H),3.01 (s, 3H); HPLC-MS calculated for C₂₄H₂₃ClN₂O₅S (M+H⁺): 487.1, found487.1.

Example 2913-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-2-yloxy)phenyl)imidazolidin-2-one

The title compound is prepared as described in Example 269 from Example290 and 2-bromopyridine. HPLC-MS calculated for C₂₉H₂₆ClN₃O₅S (M+H⁺):564.0, found 564.0.

Example 2934-(3-(2-cyanophenoxy)phenyl)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one

The title compound is prepared as described in Example 276 from Example290 and 2-fluorobenzonitrile. ¹H NMR (CDCl₃) δ 7.66 (dd, J=7.6, 1.6 Hz,1H), 7.45-7.40 (m, 1H), 7.40-7.36 (m, 2H), 7.27-7.23 (m, 3H), 7.18-7.13(m, 2H), 7.01-6.98 (m, 2H), 6.90-6.86 (m, 4H), 6.68 (dd, J=8.8, 0.8 Hz,1H), 5.22 (dd, J=9.2, 6.8 Hz, 1H), 4.06 (t, J=9.2 Hz, 1H), 3.90-3.76 (m,2H), 3.44-3.29 (m, 3H), 3.00 (s, 3H); HPLC-MS calculated forC₃₁H₂₆ClN₃O₅S (M+H⁺): 588.1, found 588.1.

The same procedure is applied towards the preparation of Example 298.See Table for spectral data.

Example 294 5-(3-(benzyloxy)phenyl)-1-(4-chlorophenyl)imidazolidin-2-one

The title compound is prepared as described for Example 288, replacing4-amino-4-chlorodiphenyl ether with 4-chloroaniline. HPLC-MS calculatedfor C₂₂H₁₉ClN₂O₂ (M+H⁺): 379.1, found 379.1.

Example 2954-(3-(benzyloxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-imidazolidin-2-one

The title compound is prepared as described for Example 289 from Example294. HPLC-MS calculated for C₂₅H₂₅ClN₂O₄S (M+14+): 485.1, found 485.1.

Example 296 3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one

The title compound is prepared as described for Example 290 from Example295. HPLC-MS calculated for C₁₈H₁₉ClN₂O₄S (M+H⁺): 395.1, found 395.1.

Example 307(4S,5S)-1-((3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-N-(piperidin-1-yl)-1H-1,2,3-triazole-4-carboxamide

(4S,5S)-1-((3-(4-Chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (40 mg, 0.082 mmol) is dissolved in CH₃CN (2 mL) and issuccessively treated with DIEA (14 μL, 0.082 mmol) and HATU (31 mg,0.082 mmol) at ambient temperature. After 5 minutes, 1-aminopiperidine(10 μL, 0.097 mmol) is added and the reaction stirred for 2 h as judgedcomplete by LC-MS. The reaction is quenched with 1 mL 1M HCl and dilutedwith water and ethyl acetate. The organic layer is washed successivelywith NaHCO₃, brine, dried over MgSO₄, filtered and concentrated.Purification by flash chromatography on silica gel (0-5%methanol/dichloromethane) gives the title compound (17 mg, 37%) as awhite film. ¹H NMR (acetone-d₆, 400 MHz) δ 8.49 (s, 1H), 8.39 (s, 1H),7.72 (s, 1H), 7.66 (d, 1H, J=9.2 Hz), 7.52 (d, 1H, J=8.5 Hz), 7.45-7.49(m, 2H), 7.30-7.33 (m, 2H), 5.85 (d, 1H, J=5.5 Hz), 5.21 (d, 2H, J=5.6Hz), 5.11 (q, 1H, J=5.6 Hz), 2.89 (t, 4H, J=5.3 Hz), 1.65 (pentet, 4H,J=6.0 Hz), 1.48-1.51 (m, 1H), 1.39-1.45 (m, 1H). HPLC-MS calculatedC₂₅H₂₃ClF₄N₆O₃ (M+H⁺): 567.2, found: 567.2.

Example 311(4S,5S)-3-(4-chlorophenyl)-5-((4-(ethylsulfonylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)oxazolidin-2-one

Meta-chloroperbenzoic acid (MCPBA) (60 mg, 0.27 mmol) is added to asolution of the sulfide (35 mg, 0.068 mmol) in CH₂Cl₂ (3 mL) at roomtemperature and stirred for 2 h. The reaction is quenched with Na₂S₂O₃and diluted with water. The organic layer is then washed with NaHCO₃,dried over MgSO₄, filtered and concentrated. Preparative HPLCpurification (C-18, 10-80% ACN/water (0.05 TFA)) gives the titlecompound (33 mg, 89%) as a colorless oil. ¹H NMR (acetone-d₆, 400 MHz) δ8.20 (s, 1H), 7.76 (s, 1H), 7.67 (d, 1H, J=9.2 Hz), 7.53 (d, 1H, J=8.5Hz), 7.43-7.49 (m, 2H), 7.29-7.35 (m, 2H), 5.83 (d, 1H, J=5.4 Hz),5.14-5.23 (m, 2H), 5.08 (ddd, 1H, J=5.8, 5.8, 4.3 Hz), 4.47 (s, 2H),2.98 (q, 2H, J=7.5 Hz), 1.28 (t, 3H, J=7.5 Hz). HPLC-MS calculatedC₂₂H₁₉ClF₄N₄O₄S (M+H⁺): 547.1, found: 547.1.

Example 324(4S,5S)-3-(4-chlorophenyl)-5-((5-(2-(diethylamino)ethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one

Step A: To a stirred solution of(4S,5R)-3-(4-chlorophenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one(prepared according to Step D of Example 64) (325 mg, 0.97 mmol) andethyl 2-(2H-tetrazol-5-yl)acetate (303 mg, 1.94 mmol) in CH₂Cl₂ at 0° C.is added triphenylphosphine (509 mg, 1.94 mmol) under an atmosphere ofnitrogen. DIAD (380 pt, 1.94 mmol) is added dropwise and the coolingbath is removed, which allowed the reaction to warm to ambienttemperature while stirring overnight. The reaction is concentrated andthe residue purified by flash chromatography on silica gel (0-40% ethylacetate/hexanes) to give 431 mg of the product as a colorless oil.

Step B: NaBH₄ (137 mg, 3.64 mmol) is added to a methanol (4 mL) solutionof the ester from Step A at 0° C. under a nitrogen atmosphere. Thecooling bath is removed and the reaction is stirred at ambienttemperature for 3 h. The reaction is quenched with a saturated solutionof NH₄Cl and diluted with water and ethyl acetate. The organic is washedwith brine, dried over MgSO₄, filtered and concentrated. Purification onsilica gel (0-5% methanol/dichloromethane) gives 369 mg of the productas a colorless oil.

Step C: Methanesulfonyl chloride (73 μL, 0.94 mmol) is added to a CH₂Cl₂(4 mL) solution of the alcohol from Step B and NEt₃ (236 μL, 1.7 mmol)at ambient temperature. After 30 minutes, the reaction is quenched witha saturated solution of NH₄Cl. The aqueous phase is extracted once withCH₂Cl₂ and the combined organics are dried over MgSO₄, filtered andconcentrated to give 440 mg of the mesylate as a colorless oil.

Step D: Performed as in Step B of Example 52 and purified by preparativeHPLC (C-18, 10-80% ACN/water (0.05% TFA)) to give 14 mg of the titlecompound as a colorless oil. ¹H NMR (acetone-d₆, 400 MHz) δ 7.43-7.47(m, 2H), 7.28-7.33 (m, 3H), 7.04 (t, 1H, J=2.2 Hz), 6.98-6.99 (m, 1H),6.91 (ddd, 1H, J=8.3, 2.6, 0.8 Hz), 5.61 (d, 1H, J=5.0 Hz), 5.32 (dd,1H, J=14.6, 5.7 Hz), 5.25 (dd, 1H, J=14.6, 5.7 Hz), 4.99 (ddd, 1H,J=5.6, 5.6, 4.2 Hz), 3.78 (s, 3H), 2.88-2.91 (m, 2H), 2.70-2.74 (m, 2H),2.51 (q, 4H, J=7.1 Hz), 0.95 (t, 6H, J=7.1 Hz). HPLC-MS calculatedC₂₄H₂₉ClN₆O₃ (M+H⁺): 485.2, found: 485.2.

Example 326(4S,5S)-3-(4-chlorophenyl)-5-((4-((diethylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one

The alcohol is prepared as described in Example 84 using propargylalcohol. The title compound is prepared as described in Steps C and D inExample 324 with purification by flash chromatography on silica gel(0-5% methanol/dichloromethane), yielding 15 mg. ¹H NMR (acetone-d₆, 400MHz) δ 8.39 (br s, 1H), 7.47-7.50 (m, 2H), 7.26-7.31 (m, 3H), 7.03 (t,1H, J=2.0 Hz), 6.97 (d, 1H, J=7.8 Hz), 6.88 (ddd, 1H, J=8.3, 2.6, 0.8Hz), 5.57 (d, 1H, J=4.8 Hz), 5.06-5.16 (m, 2H), 4.92 (q, 1H, J=4.8 Hz),4.12 (br s, 2H), 3.77 (s, 3H), 2.75 (br s, 4H), 1.23 (t, 6H, J=6.7 Hz).HPLC-MS calculated C₂₄H₂₈ClN₅O₃ (M+H⁺): 470.2, found: 470.2.

Example 334(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methyl)oxazolidin-2-one

Step 1: The ester (196 mg, 0.41 mmol, prepared using the methodsdescribed for Example 64) is dissolved in MeOH/water (3 mL, 3:1) andNaOH added (40 mg, 1 mmol). The reaction is stirred at 50° C. for 1hour, as judged complete by LC-MS, and cooled to room temperature. Thereaction is brought to pH 2 using 1M HCl, extracted 3×CH₂Cl₂, dried overMgSO₄, filtered and concentrated to give 120 mg of a white solid that isused without purification.

Step 2: The acid from Step 1 is dissolved in DMF (1 mL) under N₂.N,N′-carbonyldiimidazole (CDI, 45 mg, 0.28 mmol) is added and thereaction is stirred 30 minutes at ambient temperature, at which pointacetamidoxime (20 mg, 0.28 mmol) is added and stirred for 4 h. Anadditional 45 mg of CDI is added and the reaction is stirred at 100° C.overnight. The reaction is cooled and diluted with water anddichloromethane. The organic phase is washed successively with 1M HCl,NaHCO₃, brine, dried over MgSO₄, filtered and concentrated. Purificationby preparative HPLC (C-18, 10-70% ACN/water (0.05% TFA)) gives 15 mg ofthe title compound as a colorless oil. ¹H NMR (acetone-d₆, 400 MHz) δ7.52-7.56 (m, 2H), 7.27-7.31 (m, 3H), 7.01-7.04 (m, 2H), 6.87 (ddd, 1H,J=8.3, 2.5, 0.9 Hz), 5.45 (d, 1H, J=5.6 Hz), 4.52 (q, 1H, J=5.7 Hz),3.77 (s, 3H), 2.83-3.05 (m, 7H), 2.41 (dt, 1H, J=11.1, 2.1 Hz), 2.33(dt, 1H, J=11.1, 2.1 Hz), 2.30 (s, 3H), 1.75-1.94 (m, 2H). HPLC-MScalculated C₂₅H₂₇ClN₄O₄ (M+H⁺): 483.2, found: 483.2.

Example 336(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)methyl)oxazolidin-2-one

Step 1: CDI (30 mg, 0.18 mmol) is added to a solution of the acid(prepared in Example 334, 75 mg, 0.168 mmol) and stirred 30 minutes atambient temperature. Acetic hydrazide (14 mg, 0.18 mmol) is added andthe reaction is heated to 90° C. with stirring for 16 h. The reaction iscooled and diluted with water and ethyl acetate. The organic is washedwith brine, dried over MgSO₄, filtered and concentrated to give 28 mg ofa white film that is used without purification.

Step 2: Burgess' reagent (53 mg, 0.22 mmol) is added to a solution ofthe diacylhydrazine from Step 1 in THF under N₂. The reaction is stirredat reflux for 3 h, cooled, and concentrated. Purification of the residueby preparatory LC-MS (C-18, 10-80% ACN/water (0.05% TFA)) gives 5 mg ofthe product as a white solid. ¹H NMR (acetone-d₆, 400 MHz) δ 7.52-7.55(m, 2H), 7.27-7.29 (m, 2H), 7.00-7.02 (m, 2H), 6.86-6.88 (m, 1H), 5.44(dd, 1H, J=5.3, 2.4 Hz), 4.50-4.54 (m, 1H), 3.77 (s, 3H), 2.85-3.05 (m,6H), 2.45 (s, 3H), 2.30-2.40 (m, 2H), 1.96-2.00 (m, 1H), 1.74-1.91 (m,2H). HPLC-MS calculated C₂₅H₂₇ClN₄O₄ (M+H⁺): 483.2, found: 483.2.

Example 344(4S,5R)-3-(4-chlorophenyl)-5-((5-chloropyridin-2-yloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one

The((4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate (49 mg, 0.117 mmol), 5-chloropyridin-2-ol (45 mg, 0.35mmol), and K₂CO₃ (48 mg, 0.35 mmol) are dissolved in DMF (1.0 mL) andstirred at 35° C. for 2 h, as judged complete by LC-MS. The reaction isdiluted with water and ethyl acetate. The organic is washed with brine,dried over MgSO₄, filtered and concentrated. Separation of the N- andO-alkylated products by preparative HPLC (C-18, 10-80% ACN/water (0.05%TFA)) gave 2.5 mg of the desired product. ¹H NMR (acetone-d₆, 400 MHz) δ8.15 (d, 1H, J=2.7 Hz), 7.76 (dd, 1H, J=8.8, 2.7 Hz), 7.54-7.57 (m 2H),7.32-7.36 (m, 2H), 7.22-7.28 (m, 2H), 7.02 (tt, 1H, J=9.1, 2.3 Hz), 6.86(d, 1H, J=8.8 Hz), 5.77 (d, 1H, J=5.6 Hz), 4.85 (ddd, 1H, J=5.2, 4.0,4.0 Hz), 4.72-4.79 (m, 2H). HPLC-MS calculated C₂₁H₁₄Cl₂F₂N₂O₃ (M+H⁺):451.0, found: 451.0.

This procedure is applied towards the preparation of Example 410.

Example 363(S)-3-(4-(4-chlorophenoxy)phenyl)-1-(pyrazin-2-yl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one

To a solution of(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one(20.0 mg, 0.046 mmol) in DMF (0.5 mL) are added Cs₂CO₃ (30.1 mg, 0.092mmol) and chloropyrazine (8.25 μL, 0.092 mmol). The reaction mixture isheated at 100° C. overnight, and additional Cs₂CO₃ (30.1 mg, 0.092 mmol)and chloropyrazine (8.25 μL, 0.092 mmol) are added. After heating at100° C. for another 8 h, the reaction mixture is quenched with H₂O (5mL) and extracted with EtOAc (3×3 mL). The combined organic layer isevaporated under vacuo and purified by preparatory LC/MS to provide thetitle compound; HPLC-MS calculated for C₂₆H₁₈ClF₃N₄O₂ (M+H⁺) 511.1,found 511.1.

Example 368 benzyl1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2-oxopiperidine-4-carboxylate

A suspension of sodium hydride (7 mg, 0.18 mmol) in DMF (0.5 mL) iscooled to 0° C. Benzyl 3-oxopiperazine-1-carboxylate (40 mg, 0.1 mmol)is added slowly to the suspension, which is then stirred for 10 min.((4S,5R)-3-(4-Chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate in DMF (0.5 mL) is then added dropwise to thesuspension of the amidate and is subsequently allowed to warm to roomtemperature overnight and is then quenched with 0.1 M HCl and extractedwith ethyl acetate. The combined organics are dried over MgSO₄,filtered, and concentrated. The crude product is purified by preparativeHPLC (C-18, 10-90% ACN/water (0.05% TFA)) to give the title compound asan oil. ¹H NMR (acetone-d₆, 400 MHz) δ 7.47-7.25 (m, 9H), 7.05 (t, J=2.0Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.85 (ddd, J=8.3, 2.6, 0.9 Hz, 1H),5.44 (d, J=6.2 Hz, 1H), 5.13 (s, 2H), 4.64 (ddd, J=6.2, 5.2, 4.8 Hz,1H), 4.09-4.07 (m, 2H) 3.97-3.95 (m, 2H), 3.78-3.57 (m, 7H); HPLC-MScalculated C₂₉H₂₈ClN₃O₆ (M+H⁺) 550.2, found 550.2.

The procedure is applied towards the preparation of Example 414.

Example 376(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one

Reference for 1,2,4-oxadiazole formation: Bioorg. Med. Chem. Lett. 1999,9, 209. A solution of1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (32 mg, 0.07 mmol) in dioxane (0.5 mL) is treated withN,N′-carbonyldiimidazole and stirred at room temperature for 30 min.Acetamide oxime (10 mg, 0.13 mmol) is then added and the mixture stirredfor 2 h at room temperature then at 100° C. for 18 h. The reactionsolution is then diluted with acetonitrile and filtered through aWhatman 0.42 μM and purified by preparative HPLC (C-18, 10-90% ACN/water(0.05% TFA)) HPLC to give the title compound. ¹H NMR (acetone-d₆, 400MHz) δ 8.93 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.28 (m, 3H), 7.05-7.00 (m,2H), 6.88 (ddd, J=7.9, 2.5, 0.8 Hz, 1H), 5.62 (d, J=5.0 Hz, 1H),5.25-5.24 (m, 2H), 5.03 (ddd, J=5.7, 5.5, 4.9 Hz, 1H) 3.76 (s, 3H), 2.40(s, 3H); HPLC-MS calculated C₂₂H₁₉ClN₆O₄ (M+H⁺) 467.1, found 467.1.1.

Example 377(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one

A solution of1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylicacid (32 mg, 0.07 mmol) in dioxane (0.5 mL) is treated withN,N′-carbonyldiimidazole and stirred at room temperature for 30 min.Acetylhydrazide (10 mg, 0.13 mmol) is then added and the mixture stirredfor 2 h at room temperature. Burgess' reagent (67 mg, 0.28 mmol) is thenadded followed by THF (0.5 mL) and the mixture heated to 65° C.overnight. The cooled reaction is then evaporated to dryness andpurified by flash chromatography (4 g RediSep flash cartridge, 0-1.5%methanol/DCM) to give the title compound as a white solid. ¹H NMR(acetone-d₆, 400 MHz) δ 8.81 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.28 (m,3H), 7.04-7.00 (m, 2H), 6.88 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 5.62 (d,J=5.9 Hz, 1H), 5.23-5.21 (m, 2H), 5.03 (ddd, J=5.7, 5.4, 4.8 Hz, 1H)3.77 (s, 3H), 2.59 (s, 3H); HPLC-MS calculated C₂₂H₁₉ClN₆O₄ (M+H⁺)467.1, found 467.1.1.

Example 378(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)oxazolidin-2-one

(4S,5R)-3-(4-Chlorophenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one(40 mg, 0.12 mmol) and phenyltetrazole (17 mg, 0.12 mmol) are dissolvedin DCM (1 mL), cooled to 0° C. and are then subsequently treated withtriphenylphosphine (29 mg, 0.11 mmol) and diisopropylazodicarboxylate(0.024 mL, 0.12 mmol). The mixture is allowed to stir to roomtemperature overnight and is then purified by flash chromatography (4 gRedisep cartridge, 10-30% Ethyl acetate-hexanes) to give the titlecompound. ¹H NMR (acetone-d₆, 400 MHz) δ 8.05-8.03 (m, 2H), 7.54-7.50(m, 3H), 7.47-7.43 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.30-7.24 (m, 2H),7.09 (t, J=2.08 Hz, 1H), 7.05-7.03 (app d, J=7.8 Hz, 1H), 6.90 (ddd,J=8.3, 2.6, 0.9 Hz, 1H), 5.72 (d, J=5.1 Hz, 1H), 5.50 (dd, J=14.7, 8.7Hz, 1H), 5.43 (dd, J=14.7, 10.6 Hz, 1H), 5.12-5.08 (m, 1H), 3.76 (s,3H); HPLC-MS calculated C₂₄H₂₀ClN₅O₃ (M+H⁺) 462.1, found 462.1.

Example 380(4S,5S)-3-(4-chlorophenyl)-5-((5-(2-hydroxyethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one

A solution of ethyl2-(2-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazol-5-yl)acetate(50 mg, 0.11 mmol) [Example 379] in MeOH (1 mL) is treated with excesssodium borohydride at room temperature for 30 min. The reaction isquenched with 1 mL 0.1 M HCl and extracted with EtOAc (3×5 mL). Thecombined organics are dried over MgSO₄, filtered and concentrated togive the title compound. ¹H NMR (acetone-d₆, 400 MHz) δ 7.47-7.43 (m,2H), 7.33-7.29 (m, 3H), 7.04 (app t, J=2.0 Hz, 1H), 7.00-6.98 (app d,J=7.7 Hz, 1H), 6.90 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 5.60 (d, J=5.2 Hz,1H), 5.33 (dd, J=14.6, 6.2 Hz, 1H), 5.25 (dd, J=14.6, 4.1 Hz, 1H), 4.99(ddd, J=6.2, 5.2, 4.1 Hz, 1H), 3.89-3.76 (m, 6H), 2.99 (t, J=6.3 Hz,2H), HPLC-MS calculated C₂₀H₂₀ClN₅O₄ (M+H⁺) 430.1, found 430.1.

Example 381(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(2-morpholinoethyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one

A solution of(4S,5S)-3-(4-chlorophenyl)-5-((5-(2-hydroxyethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one(47 mg, 0.11 mmol) in DCM is cooled to 0° C. and treated withmethanesulfonyl chloride (10 μL, 0.13 mmol) followed by triethylamine(36 μL, 0.26 mmol). After 30 min., the reaction is quenched with waterand extracted with DCM, then dried over Na₂SO₄, filtered, andconcentrated to give the crude product. The crude product is thendissolved in DMF (1 mL) and treated with excess morpholine (48 μL, 0.55mmol) and heated to 100° C. overnight. The cooled reaction is thenquenched with water, basified to pH 10 and extracted with EtOAc. Thecrude product is purified by preparative HPLC (C-18, 10-90% ACN/water(0.05% TFA)) to give the title compound. ¹H NMR (acetone-d₆, 400 MHz) δ7.47-7.43 (m, 2H), 7.34-7.29 (m, 3H), 7.04 (app t, J=2.0 Hz, 1H),7.00-6.98 (app d, J=7.7 Hz, 1H), 6.90 (ddd, J=8.3, 2.6, 0.9 Hz, 1H),5.61 (d, J=5.0 Hz, 1H), 5.33 (dd, J=14.6, 5.6 Hz, 1H), 5.25 (dd, J=14.6,4.1 Hz, 1H), 4.99 (ddd, J=5.6, 5.1, 4.2 Hz, 1H), 3.78 (s, 3H), 3.55 (t,J=4.6 Hz, 4H), 2.99-2.93 (m, 2H), 2.59-2.55 (m, 2H), 2.40-2.37 (m, 4H);HPLC-MS calculated C₂₄H₂₇ClN₆O₄ (M+H⁺) 499.2, found 499.2.

Example 382(4S,5S)-3-(4-chlorophenyl)-5-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one

Step 1: To a dried 40 mL scintillation vial fitted with a Teflon coatedcap is added 3-methoxycinnamyl acetate (619 mg, 3.0 mmol), toluene (20mL), 3-(trimethylsilyl)propiolic acid (512 mg, 3.6 mmol), cesiumcarbonate (1.17 g, 3.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (346 mg, 0.3 mmol, 10 mol %). The vessel is evacuated andback-filled with Argon and then heated to 75° C. for 18 h. Upon coolingto room temperature, the reaction mixture is quenched with H₂O (5 mL)and extracted with diethyl ether (2×10 mL). The combined organics arewashed with brine, dried over MgSO₄, filtered, and concentrated. Thecrude oil is purified by flash chromatography (12 g RediSep flashcartridge, hexanes to 1.5% ethyl acetate/hexanes) to give 307 mg (42%)of ((E)-5-(3-methoxyphenyl)pent-4-en-1-ynyl)trimethylsilane as an oil.¹H NMR (acetone-d₆, 400 MHz) δ 7.23 (d, J=8.1 Hz, 1H), 6.99-6.97 (m,2H), 6.80 (m, 1H), 6.65 (dt, J=15.7, 1.7 Hz, 1H), 6.26 (dt, J=15.7, 5.7Hz, 1H), 3.8 (s, 3H), 3.19 (dd, J=5.7, 1.8 Hz, 2H), 0.16 (s, 9H).Reference: Tunge, J. A.; rayabarapu, D. K. J. Am. Chem. Soc. 2005, 127,13510-13511.

Step 2: Performed according to Example 20, Step A to give(4S,5S)-4-(3-methoxyphenyl)-5-(prop-2-ynyl)oxazolidin-2-one. HPLC-MScalculated C₁₃H₁₃NO₃ 232.1, found 232.1.

Step 3: To a 25 mL round bottom flask is placed(tetrahydro-2H-pyran-4-yl)methanol (350 mg, 3 mmol), followed bydichloromethane (DCM, 15 mL). The solution is cooled to 0° C. and isthen treated with methanesulfonyl chloride (0.24 mL, 3.15 mmol) andtriethylamine (0.88 mL, 6.3 mmol). The reaction is complete after 30min. and is then quenched with water and diluted with DCM (10 mL). Thelayers are then partitioned, and the aqueous layer is extracted with DCM(3×10 mL). The combined organics are dried over Na₂SO₄, filtered andconcentrated. The crude mesylate is then dissolved in DMF (10 mL), towhich sodium azide (410 mg, 6.3 mmol) is added and then heated to 75° C.for 4 h. The reaction is then cooled to room temperature, quenched withwater (10 mL) and extracted with diethyl ether (3×20 mL). The combinedorganics are then washed with water (3×10 mL), dried over MgSO₄,filtered, and concentrated to give 4-(azidomethyl)-tetrahydro-2H-pyranas a colorless liquid. ¹H NMR (CDCl₃, 400 MHz) δ 4.01-3.97 (m, 2H), 3.39(td, J=11.9, 2.1 Hz, 2H), 3.18 (d, J=6.8 Hz, 2H), 1.86-1.75 (m, 1H),1.67-1.64 (m, 2H), 1.40-1.29 (m, 2H).

Step 4: To an 8 mL reaction tube is placed(4S,5S)-4-(3-methoxyphenyl)-5-(prop-2-ynyl)oxazolidin-2-one (25 mg, 0.11mmol), 1:1 tBuOH:H₂O (0.5 mL), 4-(azidomethyl)-tetrahydro-2H-pyran (21mg, 0.15 mmol), CuSO₄5H₂O (catalytic), and sodium ascorbate (catalytic).The mixture is heated to 40° C. for 18 h, then quenched with water (2mL) and extracted with EtOAc (3×5 mL). The combined organics are washedwith 1M HCl (2 mL), then brine (3 mL), and are then dried over MgSO₄,filtered, and concentrated to give the crude product as an oil, which iscarried forward without further purification. HPLC-MS calculatedC₁₉H₂₄N₄O₄ (M+H⁺): 373.2, found: 373.2.

Step 5: Performed according to Example 39, Step C to give the titlecompound. ¹H NMR (acetone-d₆, 400 MHz) δ 7.87 (s, 1H), 7.46-7.42 (m,2H), 7.29-7.25 (m, 3H), 6.92-6.88 (m, 2H), 6.85 (ddd, J=8.2, 2.5, 0.9Hz, 1H), 5.45 (d, J=4.9 Hz, 1H), 4.67 (ddd, J=5.4, 5.4, 5.0 Hz, 1H),4.27 (d, J=7.2 Hz, 2H), 3.83-3.74 (m, 5H), 3.32 (d, J=5.4 Hz, 2H), 3.21(dddd, J=11.7, 11.7, 2.2, 2.2 Hz, 2H), 1.40-1.18 (m, 5H); HPLC-MScalculated C₂₅H₂₇ClN₄O₄ (M+H⁺) 483.2, found 483.2.

Example 385 is prepared in the same manner as Step 5 above fromtert-butyl 4-(azidomethyl)piperidine-1-carboxylate.

Example 384(4S,5S)-3-(4-chlorophenyl)-5-((3-(tetrahydrofuran-3-yl)isoxazol-5-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one

N-hydroxytetrahydrofuran-3-carbimidoyl chloride:Tetrahydrofuran-3-carboxaldehyde (50% solution in water, 2.5 mL, 12.5mmol) in ethanol (5.0 mL) is stirred with hydroxylamine-hydrochloride(1.3 g, 18.7 mmol) for 3 h. The reaction is quenched with 0.1 M HCl andextracted with EtOAc, dried over MgSO₄, filtered, and concentrated togive the oxime as a colorless oil. A solution of the oxime (115 mg, 1.0mmol) in DMF (1 mL) is then treated with N-chlorosuccinimide (147 mg,1.1 mmol) at 40° C. for 2 h. The reaction is then cooled to roomtemperature, poured on to ice water and extracted with diethyl ether(3×10 mL). The combined organics are dried over MgSO₄, filtered, andconcentrated to give tetrahydrofuran-3-carbonyl chloride oxime, which isused without further purification.

To a small reaction tube fitted with a screw cap is placed(4S,5S)-4-(3-methoxyphenyl)-5-(prop-2-ynyl)oxazolidin-2-one (50 mg, 0.22mmol) in tBuOH/water (1:1, 1.5 mL). Successively, copper(II) sulfatepentahydrate (2 mg, 0.012 mmol), sodium ascorbate (12 mg, 0.06 mmol),potassium bicarbonate (92 mg, 0.92 mmol), and the freshly preparedproduct described above are then added. After stirring at roomtemperature for 2 h, the reaction is then quenched with sat. ammoniumchloride, and extracted with EtOAc. The combined organics are washedwith brine, dried over MgSO₄, filtered, and concentrated to give thecrude product, which is carried forward without purification. Next, in asmall reaction tube fitted with a screw cap is placed the crudeintermediate, acetonitrile (1 mL), 4-chloro-1-iodobenzene (62 mg, 0.26mmol), copper iodide (3 mg, 0.04 mmol), N,N′-dimethylethylenediamine(9.3 μL, 0.08 mmol), and cesium carbonate (143 mg, 0.44 mmol). Thevessel is evacuated and back-filled with nitrogen, then heated to 85° C.for 4 h. The reaction is then cooled to room temperature and quenchedwith sat. ammonium chloride, extracted with EtOAc, dried over MgSO₄,filtered, and concentrated. The title compound is obtained afterpurification by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)).¹H NMR (acetone-d₆, 400 MHz) 5 (mixture of diastereomers) 8.67 (overlps, 1H), 7.50-7.43 (m, 2H), 7.30-7.27 (m, 2H), 6.97-6.96 (m, 2H),6.90-6.87 (m, 1H), 5.45 (d, J=4.8 Hz, 0.2H), 5.40 (d, J=5.8 Hz, 0.8H),4.92-4.89 (m, 0.2H), 4.68-4.63 (m, 0.8H), 4.05 (m, 1H), 3.97-3.68 (m,7H), 2.34-2.01 (m, 2H); HPLC-MS calculated C₂₃H₂₃ClN₂O₅ (M+H⁺) 455.1,found 455.1. For references to Copper catalyzed synthesis of3,5-disubstituted isoxazoles, see Hansen, T. V.; Wu, P.; Fokin, V. V. J.Org. Chem. 2005, 70, 7791-7764; Himo, F.; Lovell, T.; Hilgraf, R.;Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am.Chem. Soc. 2005, 127, 210-216.

Example 386 ethyl2-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazole-5-carboxylate

A small reaction tube fitted with a screw cap is charged with((4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate (50 mg, 0.12 mmol) and DMF (1 mL). Ethyl1H-tetrazole-5-carboxylate, sodium salt (39 mg, 0.24 mmol) is added andthe mixture is heated to 70° C. overnight. The cooled reaction isquenched with water, extracted with EtOAc, combined organics are washedwith brine, dried over MgSO₄, filtered, concentrated, and purified byflash chromatography (12 g Redisep cartridge, 30-50% EtOAc/hexanes) togive the title compound. ¹H NMR (acetone-d₆, 400 MHz) δ 7.53-7.43 (m,2H), 7.34-7.28 (m, 3H), 7.10-7.08 (m, 1H), 7.06-7.00 (m, 2H), 6.92-6.90(m, 1H), 5.67 (d, J=5.3 Hz, 1H), 5.52 (dd, J=(ddd, J=14.6, 6.5 Hz, 1H),5.47-5.41 (m, 1H), 5.11-4.99 (m, 1H), 4.46-4.41 (m, 2H), 3.76 (s, 3H),1.39-1.35 (m, 3H); HPLC-MS calculated C₂₁H₂₀ClN₅O₅ (M+H⁺) 458.1, found458.1.

Example 387(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-phenyl-1H-imidazol-1-yl)methyl)oxazolidin-2-one

A small reaction tube fitted with a screw cap is charged with((4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate (50 mg, 0.12 mmol) and DMF (1 mL). Phenylimidazole (35mg, 0.24 mmol) is added followed by cesium carbonate (39 mg, 0.12 mmol)and the mixture is heated to 70° C. overnight. The reaction is thencooled to room temperature, quenched with water and extracted withEtOAc. The combined organics are washed with water, dried over MgSO₄,filtered, concentrated, and purified by preparative HPLC (C-18, 10-90%ACN/water (0.05% TFA)) to give the title compound. ¹H NMR (acetone-d₆,400 MHz) δ 7.80-7.78 (m, 3H), 7.68 (d, J=1.2 Hz, 1H), 7.46-7.42 (m, 2H),7.34-7.17 (m, 6H), 6.96-6.93 (m, 2H), 6.89 (ddd, J=8.2, 2.5, 0.8 Hz,1H), 5.46 (d, J=5.2 Hz, 1H), 4.83 (ddd, J=6.0, 5.0, 5.0 Hz, 1H),4.70-4.69 (m, 2H), 3.72 (s, 3H); HPLC-MS calculated C₂₆H₂₂ClN₃O₃ (M+H⁺)460.1, found 460.1.

Example 389(4S,5S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one

The title compound is obtained as a side-product applying the proceduredescribed for Example 84 with propiolic acid used in place of3-fluorophenylacetylene. ¹H NMR (acetone-d₆, 400 MHz) δ 8.11 (br s, 1H),7.72 (br s, 1H), 7.49-7.42 (m, 2H), 7.33-7.30 (m, 2H), 7.22-7.15 (m,2H), 7.04-6.99 (m, 1H), 5.65 (d, J=5.3 Hz, 1H), 5.13-5.11 (m, 2H),4.99-4.97 (m, 1H); HPLC-MS calculated C₁₈H₁₃ClF₂N₄O₂ (M+H⁺): 391.1,found: 391.1.

Example 391(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-((piperidin-1-yl)methyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one

To a 10 mL round bottom flask is placed ethyl2-(((4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazole-5-carboxylate(37 mg, 0.08 mmol; prepared as described in Example 386) and MeOH (0.5mL). Sodium borohydride (5 mg, 0.135 mmol) is added and the mixture isstirred for 10 min., then quenched with water and extracted with EtOAc,dried over MgSO₄, filtered, and concentrated. The crude product is thendissolved in DCM (0.5 mL), cooled to 0° C., and treated withmethanesulfonyl chloride (7 μL, 0.08 mmol) and triethylamine (22 μL,0.16 mmol). After 30 min the reaction is quenched with 0.1 M HCl,extracted with EtOAc, dried over MgSO₄, filtered, and concentrated. Thecrude mesylate is then dissolved in DMF (0.5 mL) and is treated withpiperidine (79 μL, 0.8 mmol) at 90° C. overnight; the reaction is thencooled to room temperature and purified by preparative HPLC (C-18,10-90% ACN/water (0.05% TFA)). ¹H NMR (acetone-d₆, 400 MHz) (mixture oftetrazole regioisomers) δ 7.52 (dd, J=14.5, 9.0, Hz, 2H), 7.35-7.31 (m,2H), 7.23-7.21 (m, 2H), 7.05-6.99 (m, 1H), 5.78 (d, J=5.2 Hz, 1H), 5.39(dd, J=14.7, 5.6 Hz, 1H), 5.33 (dd, J=14.7, 4.2 Hz, 1H), 5.14-5.08 (m,1H), 3.70 (d (gem), J=14.0 Hz, 2H), 2.37-2.35 (m, 4H), 1.49-1.29 (m,6H); HPLC-MS calculated C₂₃H₂₃ClF₂N₆O₂ (M+H⁺) 489.2, found 489.2.

Example 392(4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one

To a small reaction tube is placed((4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate (50 mg, 0.12 mmol), ACN (1 mL),2-methyl-5-(2H-tetrazol-5-yl)pyridine (39 mg, 0.24 mmol), and potassiumcarbonate (33 mg, 0.24 mmol). The tube is capped and the reaction isheated to 90° C. for 4 h. The reaction is then quenched with water (2mL), and extracted with EtOAc, dried over MgSO₄, filtered, andconcentrated. The product is purified by flash chromatography (12 gRedisep, 0-10% MeOH/DCM) to give the title compound. ¹H NMR (acetone-d₆,400 MHz) δ 9.18 (br s, 1H), 8.39 (d, J=8.1 Hz, 1H), 7.58 (br s, 1H),7.47-7.44 (m, 2H), 7.29-7.23 (m, 2H), 7.02 (dddd, J=9.1, 9.1, 2.3, 2.3Hz, 1H), 5.87 (d, J=5.0 Hz, 1H), 5.54 (dd, J=14.7, 5.8 Hz, 1H), 5.46(dd, J=14.7, 4.0 Hz, 1H), 5.12 (ddd, J=5.7, 5.1, 4.0 Hz, 1H), 2.65 (s,3H); HPLC-MS calculated C₂₃H₁₇ClF₂N₆O₂ (M+H⁺) 483.1, found 483.0.

This procedure is applied toward the preparation of Example 393, Example394, Example 396, Example 401, Example 402, Example 403, and Example 407from the requisite tetrazoles and mesylates.

Example 399(4S,5S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one

A small reaction tube fitted with screw cap containing a septa ischarged with(4S,5S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)-methyl)oxazolidin-2-one(25 mg, 0.055 mmol) and DMF (0.5 mL). Potassium carbonate (25 mg, 0.18mmol) and 2-iodopropane (18 μL, 0.18 mmol) are then added and the vesselis heated to 50° C. for 4 h, then cooled to room temperature. Thereaction is quenched with water, and extracted with EtOAc, dried overMgSO₄, filtered and concentrated. The title compound is then obtainedafter flash chromatography (12 g Redisep, 30-50% EtOAc/hexanes). ¹H NMR(acetone-d₆, 400 MHz) δ 9.22 (br, s 1H), 8.72 (br, s, 1H), 8.33 (ddd,J=8.0, 1.8, 1.8 Hz, 1H), 7.52 (dd, J=7.9, 4.8 Hz, 1H), 7.46-7.42 (m,2H), 7.32 (t, J=7.6 Hz, 1H), 7.27-7.24 (m, 2H), 7.09 (app t, J=1.9 Hz,1H), 7.04 (d, J=7.7 Hz, 1H), 6.86 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 5.72(d, J=5.0 Hz, 1H), 5.51 (dd, J=14.7, 5.9 Hz, 1H), 5.44 (dd, J=14.7, 4.1Hz, 1H), 5.12 (ddd, J=5.8, 5.0, 4.2 Hz, 1H), 4.60 (septet, J=6.0 Hz,1H), 1.24 (d, J=6.0 Hz, 3H, 1.21 (d, J=6.0 Hz, 3H); HPLC-MS calculatedC₂₅H₂₃ClN₆O₃ (M+H⁺) 491.2, found 491.2.

This procedure is applied towards the syntheses of Example 406 andExample 409.

Example 400(4S,5S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one

To a 10 mL round bottom flask is charged with(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one(264 mg, 0.57 mmol) and DCM (6 mL) and is cooled to −78° C. Borontribromide (1M, 2.3 mL, 2.3 mmol) is then added dropwise, and after 30min. the cooling bath is removed and the reaction is allowed to warm toroom temperature. The reaction is quenched with water (5 mL), basifiedto pH 10 with 1N NaOH, and extracted with DCM. The combined organics aredried over Na₂SO₄, filtered, and concentrated. Purified on 40 g Redisepsilica gel cartridge with 5% MeOH/DCM to give the title compound. ¹H NMR(acetone-d6) δ 9.21 (s, 1H), 8.72 (dd, J=4.8, 1.7 Hz, 1H), 8.60 (br s,1H), 8.36 (ddd, J=6.1, 1.9, 1.9 Hz, 1H), 7.58 (dd, J=8.0, 5.0, 0.8 Hz,1H), 7.46-7.42 (m, 2H), 7.27-7.22 (m, 3H), 6.95 (d, J=7.6 Hz, 1H), 6.92(t, J=2.2 Hz, 1H), 6.82 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 5.67 (d, J=4.7Hz, 1H), 5.50 (dd, J=14.7, 5.8 Hz, 1H), 5.42 (dd, J=14.7, 3.9 Hz, 1H),5.12 (ddd, J=5.8, 4.6, 4.0 Hz, 1H), HPLC-MS calculated C₂₂H₁₇ClN₆O₃(M+H⁺) 449.1, found 449.0.

This procedure is applied towards the preparation of Example 405.

Example 4114-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1-(6-methoxypyridin-3-yl)piperazin-2-one

The title compound is prepared according to Example 52, Step B with1-(6-methoxypyridin-3-yl)piperazin-2-one (prepared via copper-mediatedcross-coupling, for a review see Angew. Chem. Int. Ed. 2003, 42, 5400).¹H NMR (acetone-d₆, 400 MHz) δ 8.10 (d, J=2.6 Hz, 1H), 7.64 (dd, J=8.8,2.7 Hz, 1H), 7.55-7.53 (m, 2H), 7.33-7.29 (m, 3H), 7.08 (dd, J=2.2, 1.8Hz, 1H), 7.04 (d, J=7.7 Hz, 1H, 6.87 (dd, J=8.3, 1.8 Hz, 1H), 5.52 (d,J=5.9 Hz, 1H), 4.62 (q, J=5.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.70(dddd, J=18.6, 12.8, 6.3, 4.9 Hz, 2H), 3.43 (d, J=16.3 Hz, 1H), 3.36 (d,J=16.3 Hz, 1H), 3.10 (dd, J=13.5, 5.5 Hz, 1H), 3.06-2.98 (m, 3H);HPLC-MS calculated C₂₇H₂₇ClN₄O₅ (M+H⁺) 523.2, found 523.0.

Example 412(4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(6-methoxypyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one

The title compound is prepared according to Example 52, Step B with1-(6-methoxypyridin-2-yl)piperazine (prepared via palladium-catalyzedcross-coupling, see Tetrahedron Lett. 2004, 45, 2057). ¹H NMR(acetone-d₆, 400 MHz) δ 7.55-7.52 (m, 2H), 7.42 (t, J=8.0 Hz, 1H)7.33-7.28 (m, 3H), 7.05-7.03 (m, 2H), 6.89-6.86 (m, 1H), 6.27 (d, J=8.1Hz, 1H), 6.01 (d, J=7.8 Hz, 1H), 5.49 (d, J=5.7 Hz, 1H), 4.57 (q, J=5.7Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.72 (ddd, J=5.0, 4.5, 4.5 Hz, 4H),2.98 (dd, J=13.4, 5.9 Hz, 1H), 2.88 (dd, J=13.4, 5.7 Hz, 1H), 2.69 (t,J=5.0 Hz, 4H); HPLC-MS calculated C₂₇H₂₉ClN₄O₄ (M+H⁺) 509.2, found509.0.

Example 416 ethyl3-((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)propanoate

A dried 25 mL round bottom flask is charged with diethyl malonate (0.11mL, 0.75 mmol) and DMF (5 mL) and is cooled to 0° C. Sodium hydride (33mg, 0.83 mmol) is then added portion-wise and after 5 min((4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methylmethanesulfonate (205 mg, 0.5 mmol) in DMF (2 mL) is then slowly addedto the solution of the malonate anion. The reaction is then heated to100° C., and after 2.5 h the reaction is subsequently cooled to roomtemperature, quenched with 0.1 M HCl, extracted with diethyl ether,dried over MgSO₄, filtered, and concentrated. The crude product ispurified by flash chromatography (12 g Redisep cartridge, 5-100%EtOAc/hexanes) to give 86 mg of the malonate adduct. The intermediate isthen transferred to a small reaction tube, dissolved in DMSO (1 mL), andcharged with lithium chloride (12 mg, 0.28 mmol) and water (3 μL, 0.14mmol). The tube is capped and heated to 160° C. overnight. The reactionis then cooled to room temperature, diluted with water, extracted withEtOAc, dried over MgSO₄, filtered, and concentrated. The crude ispurified by flash chromatography (4 g Redisep cartridge, 5-100%EtOAc/hexanes) to give the title compound. ¹H NMR (acetone-d₆, 400 MHz)δ 7.52-7.48 (m, 2H), 7.32-7.27 (m, 3H), 7.05-7.03 (dd, J=2.2, 1.9 Hz,1H), 7.01 (d, J=7.7 Hz, 1H), 6.88 (ddd, J=8.2, 2.5, 0.7 Hz, 1H), 5.35(d, J=6.1 Hz, 1H), 4.57 (ddd, J=6.9, 6.0, 6.0 Hz, 1H), 4.06 (q, J=7.1Hz, 2H), 3.77 (s, 3H), 2.63-2.50 (m, 2H), 2.29-2.15 (m, 2H), 1.18 (t,J=7.1 Hz, 3H); HPLC-MS calculated C₂₁H₂₂ClNO₅ (M+H⁺) 404.1, found 404.1.

Example 419(S)-3-(4-chlorophenyl)-1-((5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

A solution of(S)-1-(4-chlorophenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one(40 mg, 0.117 mmol, prepared by following the same procedure asdescribed in example 151 using 1-(trifluoromethyl)-3-vinylbenzene as thestarting material.) in anhydrous DMF (2 mL) is cooled down to 0° C. inan ice bath when NaH (17 mg, 60% in mineral oil, 0.423 mmol) is addedinto the solution portion wise. After the addition, the mixture isstirred at 0° C. for 10 min when a solution of3-(chloromethyl)-5-(4-methoxyphenyl)-1,2,4-oxadiazole (31.6 mg, 0.141mmol) in DMF (1 mL) is added into the mixture. The resulted mixture isallowed to warm up to room temperature and stir for 1 h. The residue ispurified by preparatory LC/MS to provide the title compound; ¹H NMR(CD₃OD, 400 MHz) δ 7.95 (d, J=9.2 Hz, 2H), 7.62 (s, 1H), 7.57 (d, J=7.6Hz, 1H), 7.48-7.39 (m, 2H), 7.31 (d, J=9.2 Hz, 2H), 7.13 (d, J=8.8 Hz,2H), 7.00 (d, J=8.8 Hz, 1H), 5.50 (dd, J=9.2, 6.0 Hz, 1H), 4.68 (m, 2H),4.07 (t, J=9.2 Hz, 1H), 3.78 (s, 3H), 3.41 (dd, J=9.0, 6.0 Hz, 1H);HPLC-MS calculated for C₂₆H₂₁ClF₃N₄O₃ (M+H⁺) 529.1, found 529.0.

Example 432(S)-3-(4-chlorophenyl)-1-(2-morpholinoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

Step A and B: Follow the procedure as described in example 172 using(S)-1-(4-chlorophenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-oneas the starting material to give(S)-3-(4-chlorophenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazo-lidin-2-one.¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.39 (m, 4H), 7.23 (d, J=8.8 Hz, 2H),7.13 (d, J=9.2 Hz, 2H), 5.22 (dd, J=9.2, 6.4 Hz, 1H), 3.99 (t, J=9.2 Hz,1H), 3.78 (t, J=5.0 Hz, 2H), 3.51-3.32 (m, 2H), 3.30 (dd, J=9.0, 6.2 Hz,1H); HPLC-MS calculated for C₁₈H₁₇ClF₃N₂O₂ (M+H⁺) 385.0, found 385.0.

Step C: Follow the procedure as described in example 175 using(S)-3-(4-chlorophenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-oneas the starting material to give(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylmethanesulfonate: HPLC-MS calculated for C₁₉H₁₉ClF₃N₂O₄ (M+H⁺) 463.0,found 463.0.

Step D: To a solution of(S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylmethanesulfonate (30 mg, 0.065 mmol) in anhydrous dichloromethane (3 mL)is added morpholine (16.9 mg, 0.194 mmol). After 3 h at roomtemperature, the residue is purified by preparatory LC/MS to provide thetitle compound; ¹H NMR (CD₃OD, 400 MHz) δ 7.71 (s, 1H), 7.62-7.53 (m,3H), 7.43 (d, J=9.2 Hz, 2H), 7.25 (d, J=9.2 Hz, 2H), 5.58 (dd, J=9.2,6.2 Hz, 1H), 4.04 (t, J=9.2 Hz, 1H), 3.95-4.59 (m, 6H), 3.49-3.26 (m,4H), 3.24 (dd, J=9.0, 6.2 Hz, 1H), 3.19-3.01 (m, 2H); HPLC-MS calculatedfor C₂₂H₂₄ClF₃N₃O₂ (M+H⁺) 454.1, found 454.0.

Example 438(S)-3-(4-chlorophenyl)-1-(2-(piperidin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

Step A: Triethylamine (683 mg, 6.75 mmol) is added to a solution ofpiperidine (274 mg, 3.22 mmol) and 2-chloroethanesulfonyl chloride (500mg, 3.07 mmol) in dichloromethane (8 mL). The reaction is stirred for 2h at room temperature. The reaction is diluted with ethyl acetate, sat.sodium bicarbonate solution is added. The organic layer is washed withbrine and dried with MgSO₄. The solvents is removed under vacuum toafford crude 1-(vinylsulfonyl)piperidine which is used directly in thenext step without further purification. HPLC-MS calculated for C₇H₁₄NO₂S(M+H⁺) 176.0, found 176.0.

Step B: Follow the same procedure as described in example 419 using1-(vinylsulfonyl)piperidine as the starting material. ¹H NMR (CD₃OD, 400MHz) δ 7.59 (s, 1H), 7.54-7.40 (m, 3H), 7.27 (d, J=9.2 Hz, 2H), 7.12 (d,J=9.2 Hz, 2H), 5.43 (dd, J=9.4, 6.2 Hz, 1H), 3.97 (t, J=9.2 Hz, 1H),3.73-3.60 (m, 2H), 3.35 (dd, J=8.8, 6.4 Hz, 1H), 3.20-3.13 (m, 6H),1.56-1.52 (m, 6H); HPLC-MS calculated for C₂₃H₂₆ClF₃N₃O₃S (M+H⁺) 516.1,found 516.1.

Example 445(S)-3-(4-chlorophenyl)-1-((6-(piperidin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

Step A: Follow the same procedure as described in example 419 using2-chloro-5-(chloromethyl)pyridine as the starting material. HPLC-MScalculated for C₂₂H₁₇ Cl₂F₃N₃O (M+H⁺) 466.0, found 466.0.

Step B: A mixture of(S)-3-(4-chlorophenyl)-1-((6-chloropyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one(34 mg, 0.073 mmol), piperidine (0.5 mL) and pyridine (2 mL) are heatedfor 2 days at 130° C. The residue is purified by preparatory LC/MS toprovide the title compound; ¹H NMR (CD₃OD, 400 MHz) δ 7.89 (dd, J=9.6,6.4 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.50-7.41 (m, 4H), 7.32-7.27 (m,3H), 7.15 (d, J=9.2 Hz, 2H), 5.45 (dd, J=9.2, 6.4 Hz, 1H), 4.34 (s, 2H),3.88 (t, J=9.2 Hz, 1H), 3.60-3.58 (m, 4H), 3.16 (dd, J=9.0, 6.2 Hz, 1H),1.72-1.61 (m, 6H); HPLC-MS calculated for C₂₇H₂₆ClF₃N₄O (M+H⁺) 515.1,found 515.1.

Example 451(S)-3-(4-chlorophenyl)-1-(2-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one

Step A: Follow the same procedure as described in example 419 using3-bromopropanenitrile as the starting material. HPLC-MS calculated forC₁₆H₁₃ClF₃N₂O (M+H⁺) 394.0, found 394.0.

Step B: A mixture of(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)-phenyl)imidazolidin-1-yl)propanenitrile(97 mg, 0.25 mmol), hydroxylamine hydrogen chloride (85.5 mg, 1.23mmol), K₂CO₃ (187 mg, 1.35 mmol) and anhydrous ethanol (4 mL) arerefluxed for 2 days. The solvent is removed under vacuum. The residue istaken into ethyl acetate, washed with sat. NaHCO₃ and brine. The organicphase is dried by Mg₂SO₄. The solvent is removed under vacuum to affordcrude(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N′-hydroxy-propanimidamidewhich is used directly in the next step without further purification.HPLC-MS calculated for C₁₉H₁₉ClF₃N₄O₂ (M+H⁺) 427.1, found 427.1.

Step C:(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)-N′-hydroxypropanimidamide(28.7 mg, 0.067 mmol) is dissolved in dichloromethane (2 mL).Cyclohexanecarbonyl chloride (14.8 mg, 0.10 mmol) and diisopropylethylamine (26.3 mg, 0.20 mmol) are then added. The reaction is stirredfor 3 h at room temperature. The reaction is diluted with ethyl acetatefollowed by quenching with sat. sodium bicarbonate solution. The organiclayer is washed with brine and dried with MgSO₄. The solvents is removedunder vacuum to afford crude(S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N′-(cyclohexanecarbonyloxy)propanimidamidewhich is used directly in the next step without further purification.HPLC-MS calculated for C₂₆H₂₉ClF₃N₄O₃ (M+H⁺) 537.1, found 537.1.

Step D: The crude product from step C is dissolved in anhydrous THF andtetrabutylammonium fluoride (67 uL) is added. The mixture is flushedwith N₂ and sealed in a microwave tube. The tube is put into a microwavereactor and heated to 100° C. for 5 min. The residue is purified bypreparatory LC/MS to provide the title compound; HPLC-MS calculated forC₂₆H₂₇ClF₃N₄O₂ (M+H⁺) 519.1, found 519.1.

Example 455(S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propane-1-sulfonamide

Step A: To a solution of 3-chloropropane-1-sulfonyl chloride (1.46 g,8.22 mmol) in anhydrous CH₂Cl₂ (20 mL) at 0° C. is addedbis-(4-methoxy-benzyl)-amine (2.22 g, 8.63 mmol) followed by Et₃N (1.68g, 10.69 mmol). After the addition, the mixture is allowed to warm toroom temperature and is stirred for 2 h. The mixture is then poured intowater (50 mL) and is extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers are concentrated and purified by flash columnchromatography (silica gel, EtOAc/hexane 0%˜50%) to provide3-chloro-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide as colorless oil.(2.7 g, 84%).

Step B: To a solution of3-chloro-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (30.0 mg, 0.075mmol) and(S)-1-(4-(4-chloro-phenoxy)-phenyl)-5-(3-(trifluoromethyl)-phenyl)-imidazolidin-2-one(20.0 mg, 0.046 mmol) in DMF (0.8 mL) is added Cs₂CO₃ (22 mg, 0.069mmol) and KI (1 mg). The resulted mixture is stirred at 80° C. for 14 hand is cooled down to room temperature. The mixture is poured into water(5 mL) and extracted with EtOAc (3×3 mL). The combined organic layersare concentrated and purified by flash column chromatography to provide(S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide(30 mg, 82%). HPLC-MS calculated for C₄₁H₃₉ClF₃N₃O₆S (M+H⁺) 794.2, found794.2.

Step C: The title compound is prepared by the same method as describedin example 164 Step C. HPLC-MS calculated for C₂₅H₂₃ClF₃N₃O₄S (M+H⁺)554.1, found 554.1.

Example 457 and Example 458(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(2-hydroxyethyl)ethanesulfonamideand(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(2-hydroxyethyl)ethanesulfonamide

To a solution of(S)-2-[3-[4-(4-chloro-phenoxy)-phenyl]-2-oxo-4-(3-trifluoromethyl-phenyl)-imidazolidin-1-yl]-ethanesulfonicacid amide (20 mg, 0.037 mmol) in acetonitrile (0.5 mL) is added Cs₂CO₃(18 mg, 0.056 mmol) followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (12mg, 0.056 mmol) and KI (1 mg). The resulting mixture is stirred at 60°C. for 14 h and is then cooled to room temperature. The mixture is thentreated with water (5 mL) and extracted with EtOAc (3×3 mL). Thecombined organic layers are concentrated and the residue is dissolved inMeOH (1 mL). To the MeOH solution is added catalytic pTSA (˜1 mg). Theresulting mixture is then stirred at room temperature for 1 h andtreated with sat. NaHCO₃ solution (3 mL). After extracting with EtOAc(3×3 mL), the combined organic layers are concentrated and purified bythin layer chromatography (silica gel, 85% EtOAc/hexane) to provideExample 457: HPLC-MS calculated for C₂₆H₂₅ClF₃N₃O₅S (M+H⁺) 584.1, found584.1; and Example 458: ¹H NMR (CDCl₃, 400 MHz) δ 7.45-7.60 (m, 4H),7.24 (d, J=8.8 Hz, 4H), 6.86 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H),5.26 (dd, J=9.2, 6.4 Hz, 1H), 4.05 (t, J=9.2 Hz, 1H), 3.72-3.90 (m, 6H),3.55 (br s, 2H), 3.48 (t, J=5.2 Hz, 4H), 3.43 (t, J=6.8 Hz, 2H), 3.36(dd, J=8.8, 6.4 Hz, 1H); HPLC-MS calculated for C₂₈H₂₉ClF₃N₃O₆S (M+H⁺)628.1, found 628.1.

Example 459(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)imidazolidin-2-one

The title compound is prepared by following the same procedure asdescribed in example 151 using 1-methoxy-3-vinylbenzene as the startingmaterial. ¹H NMR (CDCl₃, 400 MHz) δ 7.33 (d, J=9.2 Hz, 2H), 7.25 (t,J=7.6 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.84-6.89(m, 5H), 6.82 (d, J=8.8 Hz, 1H), 5.24 (dd, J=9.2, 6.4 Hz, 1H), 4.83 (brs, 1H), 3.95 (t, J=8.8 Hz, 1H), 3.77 (s, 3H), 3.35 (dd, J=8.4, 6.8 Hz,1H); HPLC-MS calculated for C₂₂H₁₉ClN₂O₃ (M+H⁺) 395.1, found 395.1.

Example 460(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)imidazolidin-2-one

A solution of(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)-imidazolidin-2-one(99 mg, 0.25 mmol) in CH₂Cl₂ (2 mL) is cooled to −78° C. when BBr₃ (1mmol, 1 mL of 1M solution in CH₂Cl₂) is added drop wise. After theaddition, the mixture is warmed to 0° C. and stirred for 1 h when MeOH(0.5 mL) is added into the mixture to quench the reaction. The reactionmixture is then treated with water (3 mL) and extracted with EtOAc (3×5mL). The combined organic layers are concentrated and purified by flashcolumn chromatography (silica gel, 0-100% EtOAc/hexane) to provide thetitled compound as a white solid (84 mg, 88%). HPLC-MS calculated forC₂₁H₁₇ClN₂O₃ (M+H⁺) 381.1, found 381.1.

Example 462(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(2-hydroxyethoxy)phenyl)imidazolidin-2-one

To a solution of(S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)-imidazolidin-2-one(26 mg, 0.068 mmol) in acetonitrile (2 mL) is added Cs₂CO₃ (50 mg, 0.15mmol) followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (30 mg, 0.14mmol). The resulting mixture is stirred at room temperature for 24 h andis then treated with water (5 mL) and extracted with EtOAc (3×3 mL). Thecombined organic layers are concentrated and the residue is dissolved inMeOH (1 mL). To the MeOH solution is added catalytic amount of pTSA (˜1mg). The resulting mixture is stirred at room temperature for 1 h and isthen treated with sat. NaHCO₃ solution (3 mL). After extracting withEtOAc (3×3 mL), the combined organic layers are concentrated andpurified by preparative thin layer chromatography (silica gel, 85%EtOAc/hexane) to provide the title compound as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.33 (d, J=9.2 Hz, 2H), 7.22-7.27 (m, 3H), 6.89 (d,J=7.6 Hz, 1H), 6.81-6.88 (m, 6H), 5.23 (dd, J=8.8, 6.0 Hz, 1H), 4.90 (brs, 1H), 3.92-4.08 (m, 5H), 2.34 (dd, J=8.8, 6.4 Hz, 1H), 2.03 (t, J=5.6Hz, 1H); HPLC-MS calculated for C₂₃H₂₁ClN₂O₄ (M+H⁺) 425.1, found 425.1.

Example 463(S)-2-(3-(4-(4-chlorophenoxy)phenyl)-4-(3-(2-hydroxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)ethanesulfonamide

Step A:2-((4S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)ethane-sulfonamideis prepared from (Example 462) and ethenesulfonic acidbis-(4-methoxy-benzyl)-amide (example 164) by using the same proceduredescribed in Example 164 step B.

Step B: A solution of2-((4S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)-ethane-sulfonamide(40 mg, 0.046 mmol) in TFA (1 mL) is stirred at room temperature for 2 hand is then concentrated. The residue is dissolved in MeOH (1 mL) andNaOH (0.09 mmol, 1M aqueous solution) is added. The mixture is stirredat room temperature for 14 h and is treated with water (3 mL) andextracted with EtOAc (3×3 ml). The combined organic layers areconcentrated and purified by flash column chromatography (silica gel,0-100% EtOAc/hexane) to provide the title compound as a white solid (20mg, 81%). ¹H NMR (CDCl₃, 400 MHz) δ 7.21-7.28 (m, 5H), 6.81-6.97 (m,7H), 5.67 (s, 2H), 5.16 (dd, J=9.2, 6.8 Hz, 1H), 3.98-4.08 (m, 2H), 3.92(m, 3H), 3.75-3.80 (m, 2H), 3.26-3.41 (m, 3H), 2.37 (br s, 1H); HPLC-MScalculated for C₂₅H₂₆ClN₃O₆S (M+H⁺) 532.1, found 532.1.

Example 464(S)—N-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylsulfonyl)acetamide

To a solution of(S)-2-[3-[4-(4-chloro-phenoxy)-phenyl]-2-oxo-4-(3-trifluoromethyl-phenyl)-imidazolidin-1-yl]ethanesulfonicacid amide (20 mg, 0.037 mmol) and acetyl chloride (6 mg, 0.076 mmol) inanhydrous CH₂Cl₂ (1 mL) is added triethylamine (7.7 mg, 0.076 mmol). Themixture is stirred at room temperature for 14 h and is then concentratedto dryness. The residue is dissolved in EtOH and treated with NaOH(0.074 mmol, 1 M aqueous solution) for 1 h. The mixture is then treatedwith water (3 mL) and extracted with EtOAc (3×3 mL). The combinedorganic layers are concentrated and purified by flash columnchromatography to provide the title compound as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.56 (m, 3H), 7.48 (m, 1H), 7.24 (d, J=8.8 Hz, 2H),7.20 (d, J=8.8 Hz, 2H), 6.86 (d, J=9.2 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H),5.26 (dd, J=9.2, 6.8 Hz, 1H), 4.00 (t, J=9.2 Hz, 1H), 3.75-3.90 (m, 2H),3.55-3.65 (m, 2H), 3.36 (dd, J=8.8, 6.8 Hz, 1H), 2.17 (s, 3H); HPLC-MScalculated for C₂₆H₂₃ClF₃N₃O₅S (M+H⁺) 582.1, found 582.1.

Example 468(S)-1-(4-chlorophenyl)-5-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one

To a solution of(S)-1-(4-chlorophenyl)-5-(3-hydroxyphenyl)imidazolidin-2-one (210 mg,0.73 mmol, prepared by using a similar procedure as described in Example460) and 3-chloropyradazine (167 mg, 1.46 mmol) in DMF (2 mL) is addedCs₂CO₃ (354 mg, 1.09 mmol). The mixture is stirred at 80° C. for 14 hand is then cooled to room temperature. The reaction mixture is thentreated with water (20 mL) and extracted with EtOAc (3×15 ml). Thecombined organic layers are washed with brine and dried (MgSO₄). Afterremoving the drying agent, the solution is concentrated and purified byflash column chromatography (silica gel, 0%˜10% MeOH/CH₂Cl₂) to providethe title compound. ¹H NMR (CDCl₃, 400 MHz) δ 8.95 (dd, J=4.4, 1.2 Hz,1H), 7.49 (dd, J=8.8, 4.4 Hz, 1H), 7.32-7.40 (m, 3H), 7.10-7.20 (m, 6H),5.28 (dd, J=8.0, 4.8 Hz, 1H), 4.70 (br s, 1H), 3.97 (t, J=8.8 Hz, 1H),3.41 (dd, J=8.8, 6.0 Hz, 1H); HPLC-MS calculated for C₁₉H₁₅ClN₄O₂ (M+H⁺)367.1, found 367.1.

Example 490 (S)-methyl3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propanoate

The title compound is prepared by the method described in Example 163,using methyl acrylate instead of vinyl methylsulfone; HPLC-MS calculatedfor C₂₆H₂₂ClF₃N₂O₄ (M+H⁺) 519.1, found 519.1.

Example 493(S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)sulfamide

Diphenyl sulfamoylcarbonimidate: To a solution of sulfamide (100.9 mg,1.05 mmol) in anhydrous acetonitrile (3.3 mL) is slowly addeddichlorodiphenoxymethane (269.1 mg, 1.00 mmol) at 0° C. The reactionmixture is stirred at room temperature overnight before removal of thesolvent. The residue is purified by chromatography to provide diphenylsulfamoylcarbonimidate (280.2 mg, 96% yield) as a white solid product;HPLC-MS calculated for C₁₃H₁₂N₂O₄S (M+H⁺) 293.1, found 293.1.

The title compound is prepared by condensing diphenylsulfamoylcarbonimidate (27.0 mg, 0.091 mmol) with(S)—N¹-(4-(4-chlorophenoxy)-phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine(37.0 mg, 0.091 mmol) [prepared from Example 173 Step A] ^(i)PrOH (1.0mL) at 80° C. for 2 h; then K₂CO₃ (25.1 mg, 0.182 mmol) is added and thereaction mixture is heated at 80° C. for another 2 h, then cooled,quenched with H₂O (5 mL), and extracted with EtOAc (3×3 mL). Thecombined organic layer is concentrated and purified by preparatory TLCto provide the title compound as a white solid; ¹H NMR (CDCl₃, 400 MHz)δ 7.59-7.47 (m, 4H), 7.26 (d, J=9.2 Hz, 2H), 7.15 (m, 3H), 6.86 (m, 4H),5.31 (dd, J=9.6, 7.6 Hz, 1H), 4.65 (br, 2H), 4.18 (t, J=9.6 Hz, 1H),3.59 (dd, J=9.6, 7.6 Hz, 1H); HPLC-MS calculated for C₂₂H₁₈ClF₃N₄O₃S(M+H⁺) 511.1, found 511.1.

Example 495(S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)methanesulfonamide

The title compound is prepared by the method described in Example 493,using methanesulfonamide instead of sulfamide and changing the reactioncondition from room temperature overnight to heating at 100° C.overnight in Step A; ¹H NMR (CDCl₃, 400 MHz) δ 7.59-7.47 (m, 4H), 7.27(d, J=9.2 Hz, 2H), 7.16 (d, J=9.2 Hz, 2H), 6.89 (d, J=9.2 Hz, 2H), 6.85(d, J=9.2 Hz, 2H), 5.31 (dd, J=9.6, 7.6 Hz, 1H), 4.17 (t, J=9.6 Hz, 1H),3.58 (dd, J=9.6, 7.6 Hz, 1H), 3.02 (s, 3H); HPLC-MS calculated forC₂₃H₁₉ClF₃N₃O₃S (M+H⁺) 510.1, found 510.1.

Example 503(S)-1-(4-(4-chlorophenoxy)phenyl)-2-(nitromethylene)-5-(3-(trifluoromethyl)phenyl)imidazolidine

1,1-Bis(methylthio)-2-nitroethylene (13.1 mg, 0.079 mmol) and(S)—N¹-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamineprepared from Example 173 Step A (16.1 mg, 0.040 mmol) are dissolved in^(i)PrOH (0.4 mL) and heated at 80° C. for 2 h. The solvent is removedand the residue is purified by preparatory LC/MS to provide the titlecompound; HPLC-MS calculated for C₂₃H₁₇ClF₃N₃O₃ (MAT) 476.1, found476.1.

Example 507(S)-1-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)urea

(S)—N-(1-(4-(4-Chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-imidazo-lidin-2-ylidene)cyanamideprepared from Example 203 (12.0 mg, 0.026 mmol) is dissolved in a mixedsolvent of 4N HCl solution (0.5 mL) and acetonitrile (0.5 mL). Thereaction mixture is heated at 80° C. for 30 minutes. The solvent isremoved en vacuo and the residue is purified by preparatory LC/MS toprovide the title compound; ¹H NMR (CDCl₃, 400 MHz) δ 9.35 (br, 1H),7.71 (br, 1H), 7.67-7.51 (m, 4H), 7.30 (d, J=8.8 Hz, 2H), 6.95 (m, 4H),6.84 (d, J=8.8 Hz, 2H), 5.67 (br, 1H), 5.25 (t, J=9.2 Hz, 1H), 4.46 (t,J=10.4 Hz, 1H), 3.97 (t, J=9.2 Hz, 1H); HPLC-MS calculated forC₂₃H₁₈ClF₃N₄O₂ (M+H⁺) 475.1, found 475.1.

Example 521(S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-cyano-4-(3-(trifluoromethyl)phenyl)imidazo-lidin-2-ylidene)cyanamide

To a solution of(S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)-phenyl)imidazolidin-2-ylidene)cyanamide[prepared from Example 203] (15.0 mg, 0.033 mmol) in 1,4-dioxane (0.5mL) is treated with excess BrCN and K₂CO₃. The reaction mixture isheated at 100° C. for 2 h, cooled, then quenched with H₂O (5 mL) andextracted with EtOAc (3×3 mL). The combined organics are evaporated envacuo and purified by preparatory LC/MS followed by preparatory TLC toprovide the title compound; HPLC-MS calculated for C₂₄H₁₅ClF₃N₅O (M+H⁺)482.1, found 482.1.

Example 522(S)-1-(2-(1H-1,2,4-triazol-3-yl)ethyl)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one

(S)-3-(3-(4-Chlorophenyl)-2-oxo-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-1-yl)propanamide(30.0 mg, 0.069 mmol) is dissolved in DMF-DMA (0.5 mL) and heated at100° C. for 1.5 h. The solvent is removed en vacuo and the residue isthen dissolved in acetic acid (0.5 mL) and treated with excess hydrazinemonohydrate. The reaction mixture is heated at 100° C. for 1 h, and thenthe solvent is removed under vacuum and the residue is purified bypreparatory LC/MS to provide the title compound; HPLC-MS calculated forC₂₃H₂₀ClN₇O₂ (M+H⁺) 462.1, found 462.1.

By repeating the procedures described in the above examples, usingappropriate starting materials, the following compounds of Formula I, asidentified in Table 1, are obtained.

TABLE 1 Physical Data Compound ¹H NMR 400 MHz (CDCl₃) Number Structureand/or MS (m/z) 1

¹H NMR (CDCl₃, 400 MHz) δ 7.28-7.37 (m, 7H), 7.25 (d, 2H), 7.46 (d, 1H),7.41 (t, 1H), 7.31 (d, 2H), 7.25 (d, 2H), 6.88 (d, 2H), 6.87 (d, 2H),5.34 (dd, 1H), 4.79 (t, 1H), 4.22 (dd, 1H); HPLC- MS calculated forC₂₁H₁₆ClNO₃ (M + H⁺) 366.1, found 366.1. 5

¹H NMR (CDCl₃, 400 MHz) δ 7.40 (d, 3H), 7.25 (d, 2H), 7.15 (d, 2H), 7.14(dd, 1H), 6.90 (d, 2H), 6.88 (d, 2H), 6.76 (t, 1H), 5.25 (dd, 1H), 4.24(br, 2H), 2.56-2.80 (m, 3H), 2.05-2.18 (m, 1H); HPLC-MS calculated forC₂₃H₁₈ClF₃N₂O₂ (M + H⁺) 447.1, found 447.1. 6

¹H NMR (CDCl₃, 400 MHz) δ 7.25 (d, 2H), 7.17 (s, 1H), 7.16 (d, 1H), 7.02(d, 2H), 6.88 (d, 2H), 6.84 (d, 2H), 6.67 (d, 1H), 4.87 (t, 1H),2.65-2.70 (m, 2H), 2.26-2.31 (m, 1H), 1.80-1.96 (m, 3H); HPLC-MScalculated for C₂₄H₂₀ClF₃N₂O₂ (M + H⁺) 461.1, found 461.1 8

¹H NMR (CDCl₃, 400 MHz) δ 7.78 (br, 1H), 7.39-7.33 (m, 7H), 7.26 (d,2H), 6.91 (d, 2H), 6.89 (d, 2H), 5.48 (s, 1H); HPLC-MS calculated forC₂₁H₁₅ClN₂O₃ (M + H⁺) 379.1, found 379.1. 10

¹H NMR (CDCl₃, 400 MHz) δ 7.20-7.33 (m, 7H), 7.11 (d, 1H), 6.90 (d, 2H),6.88 (d, 2H), 5.27 (q, 1H), 2.6-2.8 (m, 3H), 1.98-2.03 (m, 1H); HPLC-MScalculated for C₂₃H₁₆ClF₄NO₂ (M + H⁺) 450.1, found 450.1. 11

¹H NMR (CDCl₃, 400 MHz) δ 7.73 (d, 2H), 7.69 (d, 2H), 7.63 (d, 1H),7.48-7.58 (m, 5H), 7.44 (d, 2H), 5.54 (q, 1H), 4.88 (t, 1H), 4.25 (q,1H); HPLC-MS calculated for C₂₃H₁₅ClF₃NO₃ (M + H⁺) 446.1, found 446.1.12

HPLC-MS calculated for C₁₆H₁₁BrF₃NO₂ (M + H⁺) 386.0, found 386.0. 17

HPLC-MS calculated for C₂₆H₂₂ClF₃N₂O₄ (M + H⁺) 519.1, found 519.1. 18

HPLC-MS calculated for C₂₅H₂₁ClN₂O₅ (M + H⁺) 465.1, found 465.1. 19

HPLC-MS calculated for C₂₂H₁₇ClN₂O₃ (M + H⁺) 393.1, found 393.1. 21

¹H NMR (CDCl₃) δ (ppm) 7.41-7.44 (m, 4H), 7.23-7.39 (m, 10H), 6.85-6.88(m, 4H), 5.33 (d, 1H, J = 6.6 Hz), 5.13 (d, 1H, J = 6.6 Hz). HPLC-MScalculated C₂₇H₂₀ClNO₃ (M + H⁺): 442.9, found: 442.9. 22

¹H NMR (CDCl₃) δ (ppm) 7.44 (d, 2H, J = 8.3 Hz), 7.24- 7.29 (m, 2H),7.10 (d, 6H, J = 12.3 Hz), 7.01 (s, 2H), 6.86-6.90 (m, 6H), 6.00 (d, 1H,=7.4 Hz), 5.51 (d, 1H, J = 7.8 Hz). HPLC-MS calculated C₂₇H₂₀ClNO₃ (M +H⁺): 442.9, found: 442.9. ¹H NMR (CDCl₃) δ (ppm) 7.41-7.44 (m, 4H),7.23-7.39 (m, 10H), 6.85-6.88 (m, 4H), 5.33 (d, 1H, J = 6.6 Hz), 5.13(d, 1H, J = 6.6 Hz). 23

¹H NMR (acetone-d₆) δ (ppm) 7.58 (d, 2H, J = 9.1 Hz), 7.40- 7.44 9m,3H), 7.31-7.38 (m, 4H), 6.95 (dd, 4H, J = 9.1, 1.4 Hz), 5.65 (d, 1H, J =7.8 Hz), 5.14 (dq, 1H, J = 6.5, 1.3 Hz), 0.96 (d, 3H, J = 6.5 Hz).HPLC-MS calculated C₂₂H₁₈ClNO₃ (M + H⁺): 380.8, found: 380.8. 24

¹H NMR (acetone-d₆) δ (ppm) 7.55 (d, 2H, J = 9.1 Hz), 7.33- 7.42 (m,7H), 6.94 (d, 4H, J = 8.9 Hz), 5.38 (s, 1H), 1.69 (s, 3H), 0.97 (s, 3H).HPLC- MS calculated C₂₃H₂₀ClNO₃ (M + H⁺): 394.1, found: 394.1. ¹H NMR(acetone-d₆) δ (ppm) 7.58 (d, 2H, J = 9.1 Hz), 7.40-7.44 9m, 3H),7.31-7.38 (m, 4H), 6.95 (dd, 4H, J = 9.1, 1.4 Hz), 5.65 (d, 1H, J = 7.8Hz), 5.14 (dq, 1H, J = 6.5, 1.3 Hz), 0.96 (d, 3H, J = 6.5 Hz). HPLC-MScalculated C₂₂H₁₈ClNO₃ (M + H⁺): 380.8, found: 380.8. 25

¹H NMR (acetone-d₆) δ (ppm) 7.48-7.54 (m, 4H), 7.43 (t, 2H, J = 7.0 Hz),7.35-7.39 (m, 3H), 6.96 (dd, 4H, J = 8.8, 1.5 Hz), 5.75 (d, 1H, 4.7 Hz),4.93 (d, 1H, J = 4.7 Hz), 4.28- 4.36 (m, 2H), 1.32 (t, 3H, J = 7.1 Hz).HPLC-MS calculated C₂₄H₂₀ClNO₅ (M + H⁺): 438.1, found: 438.1. 27

¹H NMR (CDCl₃) δ (ppm) 7.24-7.32 (m, 7H), 7.16-7.20 (m, 2H), 6.78-6.81(m, 4H), 5.25 (dd, 1H, J = 6.4, 1.1 Hz), 4.34-4.37 (m, 1H), 3.99 (ddd,1H, J = 12.8, 2.5, 2.3 Hz), 3.74 (ddd, 1H, J = 12.8, 2.7, 2.3 Hz).HPLC-MS calculated C₂₂H₁₈ClNO₄ (M + H⁺): 396.1, found: 396.1. 29

¹H NMR (CDCl₃) δ (ppm) 7.20-7.29 (m, 9H), 7.13-7.18 (m, 5H), 6.75-6.79(m, 4H), 5.13 (d, 1H, J = 5.6 Hz), 4.61 (d, 1H, J = 12.0 Hz), 4.53 (d,1H, J = 12.0 Hz), 4.35-4.38 (m, 1H), 3.73 (dd, 1H, J = 11.0 4.1 Hz),3.65 (dd, 1H, J = 11.0, 3.6 Hz). HPLC-MS calculated C₂₉H₂₄ClNO₄ (M +H⁺): 486.1, found: 486.1. 31

¹H NMR (acetone-d₆) δ (ppm) 7.45-7.48 (m, 4H), 7.32-7.42 (m, 5H), 6.97(d, 4H, J = 8.7 Hz), 6.42 (d, 1H, J = 7.8 Hz), 5.42 (d, 1H, J = 5.6 Hz),4.55 (dd, 1H, J = 8.5, 4.7 Hz), 4.46 (dd, 1H, J = 12.5, 4.6 Hz), 4.37(dd, 1H, J = 12.4, 3.3 Hz), 3.34-3.43 (m, 1H), 1.81-1.89 (m, 2H),1.69-1.73 (m, 2H), 1.56-1.60 (m, 2H), 1.08-1.36 (m, 4H). HPLC-MScalculated C₂₉H₂₉ClN₂O₅ (M + H⁺): 521.2, found: 521.2. 32

¹H NMR (acetone-d₆) δ (ppm) 8.90 (s, 1H), 7.48-7.51 (m, 4H), 7.32-7.42(m, 5H), 7.21 (s, 1H), 6.90-6.96 (m, 5H), 6.76 (d, 1H, J = 8.2 Hz), 5.96(s, 2H), 5.52 (d, 1H, J = 5.8 Hz), 4.63-4.67 (m, 1H), 4.57 (dd, 1H, J =12.4, 4.6 Hz), 4.51 (dd, 1H, J = 12.4, 3.3 Hz). HPLC-MS calculatedC₃₀H₂₃ClN₂O₇ (M + H⁺): 559.1, found: 559.1. 36

¹H NMR (acetone-d₆) δ (ppm) 7.59 (s, 1H), 7.42-7.46 (m, 4H), 7.30-7.41(m, 5H), 6.92- 6.97 (m, 4H), 5.38 (d, 1H, J = 6.0 Hz), 4.44 (dd, 1H, J =10.6, 4.7 Hz), 3.78 (ddd, 1H, J = 14.5, 6.6, 5.0), 3.62 (ddd, 1H, J =14.5, 5.6, 4.6 Hz), 1.95 (s, 3H). HPLC-MS calculated C₂₄H₂₁ClN₂O₄ (M +H⁺): 437.1, found: 437.1. ¹H NMR (acetone-d₆) δ (ppm) 7.49-7.53 (m, 2H),7.30-7.46 (m, 7H), 6.92-6.97 (m, 4H), 5.48 (d, 1H, J = 4.8 Hz), 4.55(dd, 1H, J = 9.5, 4.7 Hz), 3.64 (dd, 2H, J = 4.9, 1.6 Hz). HPLC-MScalculated C₂₂H₁₉ClN₂O₃ (M + H⁺): 395.1, found: 395.1. 37

¹H NMR (acetone-d₆) δ (ppm) 7.44-7.47 (m, 4H), 7.32-7.41 (m, 5H),6.93-6.97 (m, 4H), 5.91 (t, 1H, J = 6.5 Hz), 5.66 (t, 1H, J = 5.1 Hz),5.49 (d, 1H, J = 5.5 Hz), 4.39 (dd, 1H, J = 9.8, 4.4 Hz), 3.75 (ddd, 1H,J = 14.7, 6.7, 4.2 Hz), 3.54 (ddd, 1H, J = 14.7, 5.7, 4.6 Hz), 3.17 (m,2H), 1.04 (t, 3H, J = 7.2 Hz). HPLC-MS calculated C₂₅H₂₄ClN₃O₄ (M + H⁺):466.2, found: 466.1. 40

¹H NMR (d₆ acetone) δ (ppm) 7.54 (d, J = 9.1 Hz, 2H), 7.48- 7.43 (m,1H), 7.37 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.29-7.25 (m,1H), 7.13- 7.08 (m, 1H), 6.98-6.95 (m, 4H), 5.55 (d, J = 5.6 Hz, 1H),4.53 (t, J = 5.9 Hz, 1H), 4.43- 4.40 (m, 1H), 4.00-3.94 (m, 1H),3.91-3.85 (m, 1H); HPLC-MS calculated C₂₂H₁₇ClFNO₄ (M + H⁺): 414.1,found: 414.0. 43

¹H NMR (d₆ acetone) δ (ppm) 7.58 (d, J = 9.1 Hz, 2H), 7.46- 7.42 (m,1H), 7.37 (d, J = 8.9 Hz, 2H), 7.21-7.10 (m, 2H), 6.98-6.95 (m, 4H),5.82 (d, J = 8.3 Hz, 1H), 5.08-5.02 (m, 1H), 4.11 (t, J = 5.3 Hz, 1H),3.36-3.30 (m, 2H); HPLC-MS calculated C₂₂H₁₇ClFNO₄ (M + H⁺): 414.1,found: 414.0. 44

¹H NMR (d₆ acetone) δ (ppm) 7.57 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 9.2Hz, 1H), 7.47-7.33 (m, 7H), 6.96-6.93 (m, 4H), 5.76 (d, J = 8.0 Hz, 1H),5.04- 4.99 (m, 1H), 4.40-4.37 (m, 1H), 3.94 (dd, J = 12.4, 3.6 Hz, 1H),3.87 (dd, J = 12.4, 3.6 Hz, 1H); HPLC-MS calculated C₂₂H₁₈ClNO₄ (M +H⁺): 396.1, found: 396.0. 45

¹H NMR (acetone-d6) δ (ppm) 7.84 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H),7.70-7.66 (m, 2H), 7.41-7.38 (m, 2H), 7.28- 7.25 (m, 2H), 7.00-6.95 (m,4H), 5.64 (d, J = 3.1 Hz, 1H), 4.86 (d, J = 3.1 Hz, 1H), 4.58 (s, 2H),4.32 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); HPLC-MS calculatedC₂₆H₂₁ClF₃NO₅ (M + H⁺: 520.1, found: 520.0. 46

¹H NMR (acetone-d6) δ (ppm) 7.77 (d, J = 7.6 Hz, 1H), 7.68-7.57 (m, 3H),7.41- 7.38 (m, 2H), 7.28-7.25 (m, 2H), 7.01-6.98 (m, 2H), 6.94- 6.90 (m,2H), 5.41 (d, J = 3.6 Hz, 1H), 5.27 (d, J = 3.6 Hz, 1H), 4.66 (d, J =16.8 Hz, 1H), 4.47 (d, J = 16.8 Hz, 1H), 4.03- 3.92 (m, 2H), 1.06 (t, J= 7.2 Hz, 3H); HPLC-MS calculated C₂₆H₂₁ClF₃NO₅ (M + H⁺: 520.1, found:520.0. 47

¹H NMR (CDCl₃) δ (ppm) 7.44-7.29 (m, 7H), 7.18-7.13 (m, 2H), 7.01-6.95(m, 1H), 6.87-6.85 (m, 2H), 5.54 (d, 1H, J = 5.7 Hz), 4.69 (d, 1H, J =12.0 Hz), 4.66 (d, 1H, J = 12.0 Hz), 4.38 (m, 1H), 3.94 (m, 2H), 3.75(s, 3H). HPLC-MS calculated C₂₄H₂₁F₂NO₄ (M + H⁺): 426.1, found: 426.1 50

¹H NMR (CDCl₃) δ (ppm) 7.38-7.36 (m, 2H), 7.34-7.23 (m, 7H), 7.12-7.09(m, 2H), 6.94-6.88 (m, 5H), 5.32 (d, J = 8.1 Hz, 1H), 4.59-4.50 (m, 3H),4.36 (d, J = 16.4 Hz, 1H), 4.26-4.22 (m, 1H), 3.70 (dd, J = 11.1, 3.0Hz, 1H), 3.58 (dd, J = 11.1 5.0 Hz, 1H); HPLC-MS calculatedC₃₀H₂₄ClF₂NO₄ (M + H⁺): 536.1, found: 536.1. 51

¹H NMR (CDCl₃) δ (ppm) 7.38-7.36 (m, 2H), 7.29-7.25 (m, 2H), 7.15-7.10(m, 2H), 6.94-6.87 (m, 5H), 5.31 (d, J = 8.1 Hz, 1H), 4.55 (d, J = 16.4Hz, 1H), 4.35 (d, J = 16.4 Hz, 1H), 4.06 (ddd, J = 8.2, 5.1, 3.1 Hz,1H), 3.70 (dd, J = 12.2, 3.1, 1H), 3.58 (dd, J = 12.2, 5.2 Hz, 1H);HPLC- MS calculated C₂₃H₁₈ClF₂NO₄ (M + H⁺): 446.1, found: 446.0.. 53

¹H NMR (acetone-d₆) δ (ppm) 7.55-7.51 (m, 2H), 7.39-7.37 (m, 2H), 7.31(t, J = 7.9 Hz, 1H), 7.08 (t, J = 2.0 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H),7.00- 6.95 (m, 4H), 6.92-6.89 (m, 1H), 5.64 (d, J = 5.4 Hz, 1H), 4.92(ddd, J = 6.6, 5.2, 5.2 Hz, 1H) 3.93-3.83 (m, 2H), 3.81- 3.70 (m, 7H),3.60 (br s, 4H), 2.15 (m, 4H); HPLC-MS calculated C₂₉H₃₂ClN₃O₄ (M + H⁺):522.2, found: 522.2. 54

¹H NMR (acetone-d₆) δ (ppm) 7.55-7.49 (m, 2H), 7.39-7.35 (m, 2H),7.31-7.27 (m, 2H), 7.03-6.94 (m, 5H), 5.81 (d, J = 6.5 Hz, 1H), 4.99(ddd, J = 6.6, 6.3. 4.1 Hz, 1H), 3.78 (dd, J = 13.7 4.0 Hz, 1H), 3.73(dd, J = 13.7, 6.7 Hz, 1H), 3.54-3.42 (m, 4H), 3.26 (td, J = 6.8, 2.5Hz, 2H), 2.35 (t, J = 8.2 Hz, 2H), 2.15-2.07 (part. Obs. By solvent,4H); HPLC-MS calculated C₂₉H₂₈ClF₂N₃O₄ (M + H⁺): 557.1, found: 557.1. 55

¹H NMR (acetone-d₆) δ (ppm) 9.00 (br s, 1H), 7.80 (br s, 1H), 7.66 (brs, 1H), 7.52-7.48 (m, 2H), 7.38-7.35 (m, 2H), 7.25-7.21 (m, 2H),7.03-6.94 (m, 5H), 5.77 (d, J = 6.0 Hz, 1H), 4.99 (ddd, J = 6.8, 6.0.4.1 Hz, 1H), 4.66 (t, J = 6.8 Hz, 1H), 3.87-3.77 (m, 2H), 3.49-3.41 (m,2H), 2.68-2.60 (m, 2H); HPLC-MS calculated C₂₈H₂₅ClF₂N₄O₃ (M + H⁺):539.2, found: 539.2. 56

¹H NMR (acetone-d₆) δ (ppm) 7.54-7.50 (m, 2H), 7.41-7.37 (m, 2H),7.28-7.25 (m, 2H), 7.05-6.96 (m, 5H), 5.77 (d, J = 6.0 Hz, 1H), 4.99(ddd, J = 6.0, 5.5. 5.5 Hz, 1H), 3.88- 3.17 (m, 10H), 2.46 (quintet, J =7.2 Hz, 2H), 2.10-2.07 (m, 4H); HPLC-MS calculated C₂₉H₃₀ClF₂N₃O₃ (M +H⁺): 542.2, found: 542.2 57

¹H NMR (acetone-d₆) δ (ppm) 9.06 (br s, 1H), 7.80 (br s, 1H), 7.66 (brs, 1H),) 7.50- 7.47 (m, 2H), 7.38-7.36 (m, 2H), 7.28 (t, J = 8.0 Hz,1H), 7.06-7.05 (m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.98-6.94 (m, 4H),6.90-6.88 (m, 1H), 5.60 (d, J = 5.7 Hz, 1H), 4.89 (app q, J = 6.2, 1H),4.66 (t, J = 6.9 Hz, 2H), 3.82-3.78 (m, 2H), 3.76 (s, 3H), 3.48 (appquintet, J = 6.8 Hz, 2H), 2.65 (t, J = 7.0 Hz, 2H); HPLC-MS calculatedC₂₉H₂₉ClN₄O₄ (M + H⁺): 533.2, found: 433.2. 58

¹H NMR (acetone-d₆) δ (ppm) 7.57-7.54 (m, 2H), 7.40-7.38 (m, 2H),7.23-7.21 (m, 2H), 7.06-6.90 (m, 5H), 5.63-5.60 (ovlp d, 1H), 4.79-4.74(ovlp dd, 1H), 4.63-4.61 (ovlp ddd, 1H), 4.14-4.10 (ovlp dd, 1H),3.91-3.84 (m, 2H), 3.55- 3.48 (m, 1H), 1.78-1.47 (m, 7H); HPLC-MScalculated C₂₇H₂₄ClF₂NO₅ (M + H⁺-THP): 431.1, found: 431.1. 59

¹H NMR (acetone-d₆) δ (ppm) 7.52 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.9Hz, 2H), 7.24-7.19 (m, 2H), 7.07-6.95 (m, 5H), 5.55 (d, J = 5.9 Hz, 1H),4.56 (dd, J = 9.9, 4.9 Hz, 1H), 3.39-3.35 (m, 5H), 2.96 (dd, J = 13.5,6.2 Hz, 1H), 2.88 (partially obs. By HOD, dd, J = 13.5, 5.4 Hz, 1H),2.53 (app t, J = 5.0 Hz, 4H), 1.41 (s, 9H); HPLC-MS calculatedC₃₁H₃₂ClF₂N₃O₅ (M + H⁺): 600.2, found: 544.1 (M-tBu + H). 60

¹H NMR (acetone-d₆) δ (ppm) 8.48 (br s, 1H), 8.40 (m, 1H), 7.67-7.64 (m,1H), 7.49-7.47 (m, 2H), 7.39-7.36 (m, 2H), 7.24 (dd, J = 7.7, 4.7 Hz,1H), 7.12-7.09 (m, 2H), 7.00-6.97 (m, 5H), 5.52 (d, J = 5.6 Hz, 1H),4.45 (ddd, J = 5.4, 5.0, 5.0 Hz, 1H), 4.21 (dd, J = 5.4, 4.6 Hz, 1H),3.15 (dd, J = 13.2, 4.9 Hz, 1H), 3.10 (dd, J = 13.2, 4.8 Hz, 1H),3.04-2.97 (m, 2H); HPLC-MS calculated C₂₉H₂₄ClF₂N₃O₃ (M + H⁺): 536.2,found: 536.2. 61

¹H NMR (acetone-d₆) δ (ppm) 7.54 (d, J = 8.4 Hz, 2H), 7.33- 7.29 (m,3H), 7.02-6.99 (m, 2H), 6.88 (d, J = 8.0 Hz 1H), 5.49-5.46 (ovlp, d, J =5.0 Hz, 1H), 4.75-4.71 (m, 1H), 4.54- 4.53 (m, 1H), 4.08-4.03 (m, 1H),3.89-3.77 (m, 2H), 3.77 (s, 3H), 3.53-3.47 (m, 1H), 1.78-1.47 (m, 7H);HPLC-MS calculated C₂₂H₂₄ClNO₅ (M + H⁺(-THP)): 334.1, found: 334.1. 62

¹H NMR (acetone-d₆) δ (ppm) 7.53 (d, J = 9.2 Hz, 2H), 7.36 (d, J = 8.8Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.04-6.88 (m, 7H) 5.48-5.43(diasteromers, d, J = 5.3 Hz, 1H), 4.75-4.71 (m, 1H), 4.54-4.53 (m, 1H),4.08-4.03 (m, 1H), 3.89-3.77 (m, 2H), 3.77 (s, 3H), 3.53- 3.47 (m, 1H),1.78-1.47 (m, 7H); HPLC-MS calculated C₂₈H₂₈ClNO₆ (M + H⁺(-THP)): 426.1,found: 426.1. 63

¹H NMR (acetone-d₆) δ (ppm) 7.78 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6Hz, 2H), 7.22 (m, 2H), 7.03 (tt, J = 9.1, 2.2 Hz, 1H), 5.74-5.72 (m,1H), 4.76- 4.71 (m, 1H), 4.67-4.66 (m, 1H), 4.15-4.11 (ovlp, d, J = 3.6Hz, 1H), 3.89-3.82 (m, 2H), 3.53-3.47 (m, 1H), 1.78- 1.47 (m, 7H);HPLC-MS calculated C₂₂H₂₀F₅NO₄ (M + H⁺(-THP)): 374.1, found: 374.0. 65

¹H NMR (acetone-d6) δ (ppm) 8.91 (s, 1H), 7.60 (s, 1H), 7.51-7.49 (m,2H), 7.35- 7.32 (m, 2H), 7.27-7.23 (m, 2H), 7.00 (tt, J = 9.1, 2.3 Hz,1H), 5.76 (d, J = 6.3 Hz, 1H), 4.65 (ddd, J = 6.8, 6.8, 3.8 Hz, 1H),3.97-3.81 (m, 2H), 3.79-3.72 (m, 2H), 3.47 (t, J = 6.9 Hz, 2H); HPLC-MScalculated C₂₁H₁₉ClF₂N₄O₂ (M + H⁺): 433.1, found: 433.1. 66

¹H NMR (acetone-d₆) δ (ppm) 7.50-7.48 (m, 1H), 7.34 (d, J = 8.7 Hz, 1H),7.26-7.18 (m, 4H), 5.53-5.51 (m, 1H), 4.72- 4.68 (m, 1H), 4.58-4.56 (m,1H), 3.98-3.92 (m, 1H), 3.81- 3.72 (m, 2H), 3.49-3.45 (m, 1H), 2.23 (s,3H), 1.78-1.47 (m, 7H); HPLC-MS calculated C₂₂H₂₂ClF₂NO₄ (M + H⁺(-THP)):354.1, found: 354.0. 67

¹H NMR (acetone-d₆) δ (ppm) 7.64 (dd, J = 11.7, 2.5 Hz, 1H), 7.54 (t, J= 8.7 Hz, 1H), 7.27-7.19 (m, 4H), 5.56 (d, J = 5.3 Hz, 1H), 4.72-4.68(m, 1H), 4.60-4.58 (m, 1H), 3.99- 3.93 (m, 1H), 3.78-3.72 (m, 2H),3.49-3.45 (m, 1H), 1.78- 1.47 (m, 7H); HPLC-MS calculated C₂₁H₁₉ClF₃NO₄(M + H⁺(-THP)): 358.1, found: 358.0. 68

¹H NMR (acetone-d₆) δ (ppm) 7.52 (d, J = 9.0 Hz, 2H), 7.32- 7.28 (m,3H), 7.03-7.01 (m, 2H), 6.89-6.86 (m, 1H), 5.44 (d, J = 5.7 Hz, 1H),4.53 (q, J = 5.7 Hz, 1H), 3.77 (s, 3H), 3.39-3.36 (m, 4H), 2.92 (dd, J =13.5, 5.9 Hz, 1H), 2.86 (dd, part. Obs by HOD, 1H), 2.51 (t, J = 5 Hz,4H), 1.42 (s, 9H); HPLC-MS calculated C₂₆H₃₂ClN₃O₅ (M + H⁺) 502.2, found502.2. 69

¹H NMR (acetone-d6) δ (ppm) 7.52 (d, 2.5 Hz, 1H), 7.32 (dd, J = 8.8, 2.5Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.23- 7.18 (m, 2H), 6.98 (tt, J =9.1, 2.3 Hz, 1H), 5.58 (d, J = 5.8 Hz, 1H), 4.68 (ddd, J = 5.9, 5.8, 5.8Hz, 1H) 3.42-3.28 (m, 4H), 2.96 (dd, J = 13.2, 5.8 Hz, 1H), 2.91-2.85(m, 5H), 2.53 (t, J = 5.2 Hz, 4H), 2.74 (s, 3H), 1.42 (s, 9H); HPLC- MScalculated C₂₆H₃₀F₂N₃O₄ (M + H⁺(-tBu): 466.1, found: 466.1. 70

¹H NMR (acetone-d6) δ (ppm) 8.12 (d, J = 2.7 Hz, 1H), 7.66 (dd, J = 8.9,2.7 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.31-7.28 (m, 2H), 7.01 (tt, J =9.1, 2.3 Hz, 1H) 5.70 (d, J = 5.9 Hz, 1H), 4.68 (ddd, J = 5.9, 5.9, 5.8Hz, 1H) 3.42- 3.28 (m, 4H), 3.06-2.91 (m, 4H), 2.56 (t, J = 5.0 Hz, 4H),1.42 (s, 9H); HPLC-MS calculated C₂₆H₂₇F₅N₃O₄ (M + H⁺(-tBu): 520.1,found: 520.1. 71

¹H NMR (acetone-d₆) δ (ppm) 7.87 (s, 1H), 7.78-7.76 (m, 1H), 7.70-7.63(m, 2H), 7.59- 7.54 (m, 2H), 7.32-7.29 (m, 2H), 5.73 (ovlp d, J = 5.2Hz, 1H), 4.76-4.72 (m, 1H), 4.65- 4.61 (m, 1H), 4.13-4.09 (m, 1H),3.88-3.83 (m, 2H), 3.52- 3.49 (m, 1H), 1.78-1.47 (m, 7H); HPLC-MScalculated C₂₂H₂₁ClF₃NO₄ (M + H⁺-THP): 371.1, found: 371.8. 73

¹H NMR (acetone-d6) δ (ppm) 7.88 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H),7.68-7.62 (m, 2H), 7.56-7.52 (m, 2H), 7.32- 7.28 (m, 2H), 5.69 (d, J =5.6 Hz, 1H), 4.60 (ddd, J = 6.6, 5.6, 5.5 Hz, 1H), 3.44-3.30 (m, 4H),3.00 (dd, J = 13.6, 6.8 Hz, 1H), 2.89 (dd, J = 13.2, 5.2 Hz, 1H),2.54-2.51 (m, 4H), 1.42 (s, 9H); HPLC- MS calculated C₂₆H₂₉ClF₃N₃O₄Exact Mass (M + H⁺(-tBu): 483.2, found: 483.9. 74

¹H NMR (acetone-d6) δ (ppm) 7.88 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H),7.68-7.62 (m, 2H), 7.56-7.52 (m, 2H), 7.32- 7.28 (m, 2H), 5.69 (d, J =5.7 Hz, 1H), 4.60 (ddd, J = 6.4, 5.6, 5.6 Hz, 1H), 3.61 (s, 3H),3.44-3.33 (m, 4H), 3.00 (dd, J = 13.6, 6.8 Hz, 1H), 2.89 (dd, J = 13.6,5.2 Hz, 1H), 2.60- 2.51 (m, 4H); HPLC-MS calculated C₂₃H₂₃ClF₃N₃O₄ ExactMass (M + H⁺): 498.1, found: 498.1. 75

¹H NMR (acetone-d6) δ (ppm) 7.88 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H),7.68-7.62 (m, 2H), 7.56-7.52 (m, 2H), 7.32- 7.28 (m, 2H), 5.69 (d, J =5.6 Hz, 1H), 4.60 (ddd, J = 6.8, 5.6, 5.2 Hz, 1H), 4.11-4.03 (m, 2H),3.44-3.33 (m, 4H), 3.00 (dd, J = 13.6, 6.6 Hz, 1H), 2.89 (dd, J = 13.6,5.2 Hz, 1H), 2.60-2.51 (m, 4H), 1.21 (t, J = 7.2 Hz, 3H); HPLC-MScalculated C₂₄H₂₅ClF₃N₃O₄ Exact Mass (M + H⁺): 512.1, found: 512.7. 76

¹H NMR (acetone-d6) δ (ppm) 7.89 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H),7.68-7.62 (m, 2H), 7.56-7.52 (m, 2H), 7.32- 7.28 (m, 2H), 5.69 (d, J =5.7 Hz, 1H), 4.60 (ddd, J = 6.5, 5.6, 5.5 Hz, 1H), 3.81 (d, J = 6.4 Hz,2H), 3.44-3.33 (m, 4H), 3.00 (dd, J = 13.6, 6.6 Hz, 1H), 2.89 (dd, J =13.6, 5.2 Hz, 1H), 2.60-2.51 (m, 4H), 1.95-1.86 (m, 1H), 0.92 (t, J =6.8 Hz, 6H); HPLC-MS calculated C₂₆H₂₉ClF₃N₃O₄ Exact Mass (M + H⁺):540.2, found: 539.8. 77

¹H NMR (acetone-d₆) δ (ppm) 7.77-7.75 (m, 2H), 7.70-7.67 (m, 2H), 7.33(t, J = 7.9 Hz, 1H), 7.05-7.00 (m, 2H), 6.90 (dd, J = 8.2, 1.9 Hz, 1H),5.58 (ovlp d, J = 4.8 Hz, 1H), 4.76- 4.71 (m, 1H), 4.61-4.57 (m, 1H),4.11-4.07 (m, 1H), 3.88- 3.83 (m, 2H), 3.78 (s, 3H), 3.52-3.49 (m, 1H),1.78-1.47 (m, 7H); HPLC-MS calculated C₂₃H₂₄N₂O₅ (M + H⁺-THP): 325.1,found: 325.1. 78

¹H NMR (acetone-d6) δ (ppm) 7.82 (s, 1H), 7.77-7.64 (m, 7H), 7.40-7.36(m, 2H), 7.09-7.05 (m, 2H), 5.82 (d, J = 4.8 Hz, 1H), 4.70-4.62 (m, 3H),3.97 (d, J = 4.1 Hz, 2H); HPLC-MS calculated C₂₅H₁₈ClF₄N₂O₃ (M + H⁺:471.1, found: 470.8. 79

¹H NMR (acetone-d₆) δ (ppm) 7.51 (d, J = 9.0 Hz, 2H), 7.46- 7.39 (m,3H), 7.32-7.23 (m, 4H), 7.12-7.07 (m, 3H), 5.57 (d, J = 5.4 Hz, 1H),4.69-4.62 (gem, d, J = 12.0 Hz, 2H), 4.58 (ddd, J = 5.7, 3.8, 3.4 Hz,1H), 3.96-3.89 (m, 2H); HPLC-MS calculated C₂₃H₁₈ClF₂NO₃ (M + H⁺) 430.1,found: 430.1. 80

¹H NMR (acetone-d6) δ (ppm) 7.82 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.68(d, J = 7.9 Hz, 1H), 7.65-7.61 (m, 1H), 7.56-7.52 (m, 2H), 7.32-7.28 (m,2H), 7.10-6.97 (m, 2H), 5.71 (d, J = 5.3 Hz, 1H), 4.69- 4.60 (m, 3H),3.95 (d, J = 3.8 Hz, 2H); HPLC-MS calculated C₂₄H₁₈ClF₄N₂O₃ (M + H⁺:480.1, found: 479.7. 81

¹H NMR (acetone-d6) δ (ppm) 7.83 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.69(d, J = 7.9 Hz, 1H), 7.65-7.61 (m, 1H), 7.55-7.49 (m, 3H), 7.32-7.28 (m,2H), 7.07-6.69 (m, 2H), 5.72 (d, J = 5.2 Hz, 1H), 4.73- 4.64 (m, 3H),4.01 (d, J = 3.6 Hz, 2H); HPLC-MS calculated C₂₄H₁₇ClF₅N₂O₃ (M + H⁺:498.1, found: 497.7. 82

¹H NMR (acetone-d6) δ (ppm) 8.85 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 8.8,2.8 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 7.6Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.26 (d, J= 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.86 (d, J = 5.2 Hz, 1H), 4.73(ddd, J = 5.1, 3.7, 3.6 Hz, 1H), 4.59-4.53 (m, 2H), 3.94 (d, J = 3.6 Hz,2H), 3.78 (s, 3H); HPLC-MS calculated C₂₅H₂₀F₃N₃O₄ (M + H⁺: 484.1,found: 484.1. 85

¹H NMR (acetone-d6) δ (ppm) 7.83 (s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.69(d, J = 7.9 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 8.9 Hz, 2H),7.30-7.28 (m, 2H), 5.75 (d, J = 5.81 (d, J = 5.0 Hz, 1H), 5.13-5.06 (m,2H), 5.00 (ddd, J = 5.1, 5.0, 4.5 Hz, 1H), 3.59 (br s, 3H), 3.09 (br s,3H); HPLC-MS calculated C₂₂H₂₁ClF₃N₅O₂ (M + H⁺: 480.1, found: 480.1. 86

¹H NMR (acetone-d6) δ (ppm) 8.32-8.31 (m, 2H), 7.92 (s, 1H), 7.80 (m,1H), 7.67- 7.64 (m, 2H), 7.57-7.55 (m, 2H), 7.32-7.28 (m, 2H), 6.57-6.56 (m, 1H), 5.75-5.74 (m, 1H), 4.67-4.65 (m, 1H), 3.79- 3.73 (m, 4H),3.06-3.02 (m, 1H), 2.94-2.89 (m, 1H), 2.63- 2.52 (m, 4H),; HPLC-MScalculated C₂₅H₂₃ClF₃N₅O₂ Exact Mass (M + H⁺): 518.1, found: 518.1. 90

¹H NMR (CDCl₃) δ (ppm) 7.33-7.40 (m, 4H), 7.24-7.30 (m, 2H), 7.14-7.17(m, 1H), 6.99-7.07 (m, 2H), 6.86-6.92 (m, 4H), 5.34 (br s, 1H), 4.41 (brs, 1H), 3.12 (d, 1H, J = 13.1 Hz), 2.98 (d, 1H, J = 13.0 Hz), 2.62-2.90(m, 7H), 1.76-2.3 (m, 7H), 1.26-1.27 (m, 1H). HPLC-MS calculatedC₂₉H₃₁ClFN₃O₃ (M + H⁺): 524.2, found: 524.2 91

¹H NMR (CDCl₃) δ (ppm) 7.33 (d, 2H, J = 9.0 Hz), 7.24- 7.30 (m, 4H),6.83-6.91 (m, 6H), 5.26 (d, 1H, J = 6.5 Hz), 4.40-4.43 (m, 1H), 4.05(dd, 1H, J = 12.8, 3.0 Hz), 3.81 (dd, 1H, J = 12.8, 3.2 Hz), 3.77 (s,3H). HPLC-MS calculated C₂₃H₂₀ClNO₅ (M + H⁺): 426.1, found: 426.1. 92

¹H NMR (CDCl₃) δ (ppm) 7.31-7.37 (m, 3H), 7.24-7.28 (m, 2H), 7.10 (d,1H, J = 7.7 Hz), 6.99-7.04 (m, 2H), 6.86- 6.92 (m, 4H), 4.43 (dd, 1H, J= 11.7, 3.0 Hz), 2.78 (d, 2H, J = 5.9 Hz), 2.61 (br s, 4H), 2.47 (br s,4H), 2.30 (s, 3H). HPLC-MS calculated C₂₇H₂₇ClFN₃O₃ (M + H⁺): 496.2,found: 496.2. 93

¹H NMR (CDCl₃) δ (ppm) 7.30-7.35 (m, 3H), 7.22-7.27 (m, 2H), 7.11 (d,1H, J = 7.7 Hz), 6.98-7.05 (m, 2H), 6.84- 6.87 (m, 4H), 5.29 (d, 1H, J =6.3 Hz), 4.38-4.42 (m, 1H), 3.30 (dd, 1H, J = 13.7, 3.2 Hz), 3.11 (dd,1H, J = 13.3, 5.1 Hz), 2.22 (br s, 1H). HPLC-MS calculated C₂₂H₁₈ClFN₂O₃(M + H⁺): 413.2, found: 413.1. 94

¹H NMR (acetone-d₆) δ (ppm) 7.43-7.50 (m, 3H), 7.35-7.39 (m, 2H),7.28-7.33 (m, 2H), 7.11 (dt, 1H, J = 8.5, 2.1 Hz), 6.96 (d, 4H, J = 8.7Hz), 6.42 (d, 1H, J = 7.5 Hz), 5.48 (d, 1H, J = 5.7 Hz), 4.57-4.61 (m,1H), 4.48 (dd, 1H, J = 12.5, 4.6 Hz), 4.38 (dd, 1H, J = 12.4, 3.4 Hz),3.34-3.43 (m, 1H), 1.81- 1.89 (m, 2H), 1.69-1.73 (m, 2H), 1.57-1.60 (m,2H), 1.09- 1.36 (m, 4H). HPLC-MS calculated C₂₉H₂₈ClFN₂O₅ (M + H⁺):539.2, found: 539.2. 95

¹H NMR (acetone-d₆) δ (ppm) 7.43-7.50 (m, 3H), 7.28-7.39 (m, 5H), 7.11(dt, 1H, J = 8.6, 2.1 Hz), 6.94-6.98 (m, 4H), 6.39 (d, 1H, J = 6.4 Hz),5.48 (d, 1H, J = 5.7 Hz), 4.58-4.61 (m, 1H), 4.47 (dd, 1H, J = 12.4, 4.6Hz), 4.38 (dd, 1H, J = 12.4, 3.4 Hz), 3.69-3.77 (sept, 1H, J = 7.0 Hz),1.12 (m, 6H). HPLC-MS calculated C₂₆H₂₄ClFN₂O₅ (M + H⁺): 499.1, found:499.2. 96

¹H NMR (acetone-d₆) δ (ppm) 7.51 (d, J = 9.0 Hz, 2H), 7.38- 7.29 (m,7H), 7.15 (d, J = 6.2 Hz, 2H), 7.02-6.96 (m, 5H), 5.58 (d, J = 5.4 Hz,1H), 4.71- 4.64 (gem, d, J = 12.1 Hz, 2H), 4.67 (ddd, J = 5.6, 3.8, 3.5Hz, 1H), 3.92 (m, 1H); HPLC-MS calculated C₂₉H₂₂ClF₂NO₄ (M + H⁺): 522.1,found: 522.1. 97

¹H NMR (CDCl₃) δ (ppm) 7.33-7.38 (m, 3H), 7.24-7.27 (m, 2H), 7.10 (d,1H, J = 7.7 Hz), 6.99-7.03 (m, 2H), 6.86- 6.92 (m, 4H), 5.20 (d, 1H, J =5.5 Hz), 4.39 (dt, 1H, J = 5.7, 5.7 Hz), 2.23 (s, 6H). HPLC-MScalculated C₂₄H₂₂ClFN₂O₃ (M + H⁺): 441.1, found: 441.1. 98

¹H NMR (CDCl₃) δ (ppm) 7.30-7.36 (m, 3H), 7.24-7.28 (m, 2H), 7.17 (d,1H), 7.06 (d, 1H, J = 9.2 Hz), 7.01 (dt, 1H, J = 8.4, 2.0 Hz), 6.85-6.91(m, 4H), 5.30 (d, 1H, J = 5.7 Hz), 5.03 (t, 1H, J = 6.1 Hz), 4.41- 4.44(m, 1H), 3.89-3.96 (m, 1H), 3.61-3.66 (m, 5H), 3.29- 3.39 (m, 4H).HPLC-MS calculated C₂₇H₂₅ClFN₃O₅ (M + H⁺): 525.1, found: 525.1. 100

¹H NMR (CDCl₃) δ (ppm) 7.31-7.35 (m, 3H), 7.23-7.27 (m, 2H), 7.10 (d,1H, J = 7.8 Hz), 6.99-7.04 (m, 2H), 6.86- 6.91 (m, 4H), 5.29 (d, 1H, J =6.3 Hz), 4.42-4.45 (m, 1H), 3.53 (d, 2H, J = 2.3 Hz), 3.19 (dd, 1H, J =13.1, 4.1 Hz), 3.02 (dd, 1H, J = 13.1, 4.8 Hz), 2.27 (t, 1H, J = 2.4Hz). HPLC-MS calculated C₂₅H₂₀ClFN₂O₃ (M + H⁺): 451.1, found: 451.1. 102

¹H NMR (CDCl₃) δ (ppm) 8.60 (d, 1H, J = 1.7 Hz), 8.55 (dd, 1H, J = 4.8,1.5 Hz), 7.67 (dt, 1H, J = 7.8, 1.7 Hz), 7.24- 7.34 (m, 7H), 6.98-7.02(m, 2H), 6.94 (t, 1H, J = 1.9 Hz), 6.86-6.92 (m, 4H), 5.20 (d, 1H, J =6.3 Hz), 4.41 (ddd, 1H, J = 6.2, 4.6, 4.6 Hz), 3.95 (d, 1H, J = 13.5Hz), 3.85 (d, 1H, J = 13.5 Hz), 3.11 (dd, 1H, J = 13.1, 4.0 Hz), 2.90(dd, 1H, J = 13.1, 4.8 Hz). HPLC-MS calculated C₂₈H₂₃ClFN₃O₃ (M + H⁺):504.1, found: 504.1. 103

¹H NMR (acetone-d₆) δ (ppm) 7.50-7.54 (m, 2H), 7.34-7.38 (m, 2H), 7.30(t, 1H, J = 7.8 Hz), 7.01-7.03 (m, 2H), 6.93- 6.98 (m, 4H), 6.88 (dd,1H, J = 8.8, 2.4 Hz), 5.38 (d, 1H, J = 5.7 Hz), 4.48 (app q, 1H, J = 5.8Hz), 3.78 (s, 3H), 2.75- 2.89 (m, 2H), 2.55 (br s, 4H), 2.35 (br s, 4H),2.17 (s, 3H). HPLC-MS calculated C₂₈H₃₀ClN₃O₄ (M + H⁺): 508.2. found:508.2. 104

¹H NMR (acetone-d₆) δ (ppm) 7.51-7.55 (m, 2H), 7.35-7.39 (m, 2H),7.20-7.25 (m, 2H), 6.95-7.00 (m, 5H), 5.56 (d, 1H, J = 6.0 Hz), 4.58(ddd, 1H, J = 6.1, 6.1, 6.0 Hz), 3.55-3.65 (m, 4H), 2.93 (dd, 1H, J =13.4, 6.2 Hz), 2.85 (dd, 1H, J = 13.4, 5.5 Hz), 2.55 (br s, 4H). HPLC-MScalculated C₂₆H₂₃ClF₂N₂O₄ (M + H⁺): 501.1, found: 501.1. 105

¹H NMR (acetone-d6) δ (ppm) 7.50 (d, J = 8.9 Hz, 2H), 7.37 (d, 8.9 Hz,2H), 7.22 (m, 2H), 7.02-6.96 (m, 5H), 5.55 (d, J = 6.1 Hz, 1J), 4.65(dd, J = 11.2, 5.9 Hz), −3.68-3.20 (m, 8H), 3.16 (dd, J = 13.9, 4.8 Hz,1H), 3.10 (dd, 13.8, 6.1 Hz, 1H), 2.93 (s, 3H). HPLC-MS calculatedC₂₇H₂₆ClF₂N₃O₃ (M + H⁺): 514.2, found: 514.1. 107

¹H NMR (acetone-d₆) δ (ppm) 7.47-7.50 (m, 2H), 7.40-7.45 (m, 1H),7.30-7.39 (m, 4H), 7.11 (dt, 1H, J = 8.9, 1.8 Hz), 6.94-6.97 (m, 4H),5.55 (d, 1H, J = 6.4 Hz), 5.02-5.07 (m, 1H), 4.69 (dd, 1H, J = 7.4,5.4), 3.70-4.06 (m, 8H), 3.25-3.49 (m, 4H), 2.23-2.31 (m, 1H), 1.93-2.01(m, 1H), 1.82-1.92 (m, 2H). HPLC-MS calculated C₃₁H₃₁ClFN₃O₅ (M + H⁺):580.2, found: 580.2. 108

¹H NMR (acetone-d₆) δ (ppm) 7.48-7.50 (m, 2H), 7.41-7.45 (m, 1H),7.34-7.39 (m, 3H), 7.30 (dt, 1H, J = 9.8, 2.2 Hz), 7.10 (dt, 1H, J =8.3, 2.1 Hz), 6.93-6.97 (m, 4H), 5.53 (d, 1H, J = 6.1 Hz), 4.67 (dq, 1H,J = 6.3, 2.0 Hz), 4.37 (dq, 1H, J = 7.3, 1.6 Hz), 3.86 (q, 1H, J = 7.5Hz), 3.73-3.78 (m, 1H), 3.40-3.70 (m, 5H), 3.11-3.25 (m, 7H), 2.07-2.16(m, 1H), 1.83-1.95 (m, 2H), 1.55-1.64 (m, 1H). HPLC-MS calculatedC₃₁H₃₃ClFN₃O₄ (M + H⁺): 566.2, found: 566.2. 110

¹H NMR (CDCl₃) δ (ppm) 7.33-7.37 (m, 2H), 7.23-7.27 (m, 2H), 6.80-6.86(m, 2H), 6.76 (tt, J = 8.7, 2.3 Hz, 1H), 5.27 (ovlp d, 1H, J = 5.0 Hz),4.64-4.70 (m, 1H), 4.40-4.44 (m, 1H), 3.99-4.07 (m, 1H), 3.82-3.89 (m,1H), 3.75 (ddd, 1H, J = 29.3, 11.5, 4.3 Hz), 3.51-3.57 (m, 1H),1.70-1.79 (m, 2H), 1.50-1.62 (m, 4H). HPLC-MS calculated C₂₁H₂₀ClF₂NO₄(M + H⁺): 424.1, found: 424.1. 111

¹H NMR (CDCl₃) δ (ppm) 7.31-7.36 (m, 3H), 7.24-7.27 (m, 2H), 7.10 (d,1H, J = 7.8 Hz), 6.98-7.04 (m, 2H), 6.86- 6.91 (m, 4H), 5.15 (d, 1H, J =5.8 Hz), 4.42 (q, 1H, J = 5.8 Hz), 3.71 (t, 4H, J = 4.6 Hz), 2.77 (d,2H, J = 5.9 Hz). 2.59 (br s, 5H), 2.49-2.52 (m, 11H). HPLC-MS calculatedC₃₂H₃₆ClFN₄O₄ (M + H⁺): 595.2, found: 595.2. 112

¹H NMR (CDCl₃) δ (ppm) 7.26-7.28 (m, 2H), 7.10 (d, 2H, J = 8.4 Hz),6.83-6.89 (m, 2H), 6.74 (dddd, 1H, J = 8.7, 8.7, 2.3, 2.3 Hz), 5.28(ovlp d, 1H, J = 5.1 Hz), 4.67-4.72 (m, 1H), 4.40-4.44 (m, 1H), 3.99-4.08 (m, 1H), 3.84-3.91 (m, 1H), 3.77 (ddd, 1H, J = 27.6, 11.4, 4.4 Hz),3.53-3.58 (m, 1H), 2.28 (s, 3H), 1.71-1.82 (m, 2H), 1.52-1.64 (m, 4H).HPLC-MS calculated C₂₂H₂₃F₂NO₄ (M + H⁺): 404.2, found: 404.2 113

¹H NMR (CDCl₃) δ (ppm) 7.28-7.31 (m, 2H), 7.21-7.25 (m, 2H), 6.81-6.88(m, 2H), 6.77 (tt, 1H, J = 8.7, 2.2 Hz), 5.35 (d, 1H, J = 6.1 Hz), 4.35(ddd, 1H, J = 6.0, 2.9, 2.9), 4.03-4.08 (m, 1H), 3.80 (ddd, 1H, J =12.7, 7.7, 2.8 Hz), 2.89 (dd, 1H, J = 7.5, 5.2 Hz). HPLC-MS calculatedC₁₆H₁₂ClF₂NO₃ (M + H⁺): 340.1, found: 340.2. 114

¹H NMR (CDCl₃) δ (ppm) 7.29-7.40 (m, 7H), 7.23-7.25 (m, 2H), 6.74-6.77(m, 3H), 5.22 (d, 1H, J = 5.2 Hz), 4.69 (d, 1H, J = 12.0 Hz), 4.60 (d,1H, J = 12.0 Hz), 4.38 (q, 1H, J = 4.8 Hz), 3.80 (dd, 1H, J = 10.8, 4.6Hz), 3.74 (dd, 1H, J = 10.8, 3.5 Hz). HPLC-MS calculated C₂₃H₁₈ClF₂NO₃(M + H⁺): 430.1, found: 430.1. 115

¹H NMR (CDCl₃) δ (ppm) 7.35 (d, 2H, J = 8.9 Hz), 7.26 (d, 2H, J = 9.0Hz), 6.82-6.87 (m, 2H), 6.77 (tt, 1H, J = 8.6, 2.2 Hz), 5.18 (d, 1H, J =5.5 Hz), 4.40 (q, 1H, J = 5.6 Hz), 3.66-3.75 (m, 4H), 2.73-2.82 (m, 2H),2.56 (t, 4H, J = 4.6 Hz). HPLC-MS calculated C₂₀H₁₉ClF₂N₂O₃ (M + H⁺):409.1, found: 409.1. 116

¹H NMR (CDCl₃) δ (ppm) 7.48 (s, 1H), 7.31-7.34 (m, 2H), 7.25-7.28 (m,2H), 7.07 (s, 1H), 6.90 (s, 1H), 6.75- 6.84 (m, 3H), 5.17 (d, 1H, J =6.0 Hz), 4.36 (q, 1H, J = 5.2 Hz), 4.03 (t, 2H, J = 6.8 Hz), 3.05 (dd,1H, J = 13.2, 4.0 Hz), 2.89 (dd, 1H, J = 13.2, 5.1 Hz), 2.59-2.72 (m,2H), 1.95 (pentet, 2H). HPLC-MS calculated C₂₂H₂₁ClF₂N₄O₂ (M + H⁺):447.1. found: 447.1. 117

¹H NMR (CDCl₃) δ (ppm) 7.32-7.37 (m, 3H), 7.23-7.27 (m, 2H), 7.10 (d,1H, J = 7.7 Hz), 6.99-7.03 (m, 2H), 6.86- 6.91 (m, 4H), 5.17 (d, 1H, J =5.6 Hz), 4.69 (d, 1H, J = 6.5 Hz), 4.40 (q, 1H, J = 5.7 Hz), 4.17 (br s,1H), 2.96 (dd, 1H, J = 13.0, 6.3 Hz), 2.87-2.92 (m, 1H), 2.82 (dd, 1H, J= 13.0, 5.3 Hz), 2.71 (dd, 1H, J = 9.6, 6.5 Hz), 2.58 (d, 1H, J = 8.0Hz), 2.45 (q, 1H, J = 8.2 Hz), 2.20- 2.28 (m, 1H), 1.56-1.64 (m, 1H),1.44 (s, 9H). HPLC-MS calculated C₃₁H₃₃ClFN₃O₅ (M + H⁺): 582.2, found:582.2. 118

¹H NMR (CDCl₃) δ (ppm) 7.32-7.37 (m, 3H), 7.24-7.27 (m, 2H), 7.11 (d,1H, J = 7.7 Hz), 7.00-7.04 (m, 2H), 6.86- 6.90 (m, 4H), 5.15 (d, 1H, J =5.8 Hz), 4.47 (br s, 1H), 3.43 (br s, 4H), 2.83 (br s, 2H), 2.53 (br s,4H), 1.45 (s, 9H). HPLC-MS calculated C₃₁H₃₃ClFN₃O₅ (M + H⁺): 582.2,found: 582.2. 119

¹H NMR (CDCl₃) δ (ppm) 7.52-7.59 (m, 4H), 7.34-7.39 (m, 1H), 7.10 (d,1H, J = 6.8 Hz), 7.01-7.06 (m, 2H), 5.35 (ovlp d, 1H, J = 4.9 Hz), 4.67-4.73 (m, 1H), 4.48 (pentet, 1H, J = 4.8 Hz), 4.05 (ddd, 1H, J = 19.6,11.1, 4.6 Hz), 3.83- 3.90 (m, 1H), 3.77 (ddd, 1H, J = 32.1, 11.6, 4.1Hz), 3.53- 3.58 (m, 1H), 1.70-1.77 (m, 2H), 1.52-1.62 (m, 4H). HPLC-MScalculated C₂₂H₂₁F₄NO₄ (M + H⁺): 440.1, found: 440.1. 120

¹H NMR (CDCl₃) δ (ppm) 7.31-7.38 (m, 3H), 7.24-7.28 (m, 2H), 7.10 (d,1H, J = 7.7 Hz), 7.00-7.04 (m, 2H), 6.86- 6.92 (m, 4H), 5.10 (d, 1H, J =5.7 Hz), 4.41 (q, 1H, J = 5.8 Hz), 2.81-2.86 (m, 5H), 2.75 (dd, 1H, J =13.7, 6.1 Hz), 2.60-2.71 (m, 4H). HPLC-MS calculated C₂₆H₂₄ClFN₂O₃S (M +H⁺): 499.1, found: 499.1. 121

¹H NMR (CDCl₃) δ (ppm) 7.30-7.36 (m, 3H), 7.23-7.27 (m, 2H), 7.10 (d,1H, J = 7.7 Hz), 6.98-7.04 (m, 2H), 6.85- 6.90 (m, 4H), 5.22 (d, 1H, J =4.7 Hz), 4.41 (br s, 1H), 3.58 (br s, 1H), 2.76-3.00 (m, 4H), 2.54 (brs, 2H), 2.17 (br s, 1H), 2.00 (br s, 3H), 1.59 (br s, 1H). HPLC-MScalculated C₂₆H₂₅ClFN₃O₃ (M + H⁺): 482.2, found: 482.2. 122

¹H NMR (CDCl₃) δ (ppm) 7.31-7.37 (m, 3H), 7.24-7.28 (m, 2H), 7.11 (d,1H, J = 7.7 Hz), 6.99-7.04 (m, 2H), 6.86- 6.91 (m, 4H), 5.15 (d, 1H, J =5.8 Hz), 4.44 (q, 1H, J = 5.9 Hz), 2.94 (br s, 4H), 2.73-2.82 (m, 2H),2.57 (br s, 4H), 2.37 (br s, 1H). ). HPLC-MS calculated C₂₆H₂₅ClFN₃O₃(M + H⁺): 482.2, found: 482.2. 123

¹H NMR (CDCl₃) δ (ppm) 7.49-7.54 (m, 4H), 7.27-7.39 (m, 6H), 6.99 (ddd,1H, J = 8.4, 8.4, 2.5 Hz), 6.94 (d, 1H, J = 7.7 Hz), 6.85 (dt, 1H, J =9.2, 2.0, 2.0 Hz), 5.28 (d, 1H, J = 6.0 Hz), 4.37 (ddd, 1H, J = 5.9,4.3, 4.3 Hz), 3.93 (d, 1H, J = 13.2 Hz), 3.82 (d, 1H, J = 13.2 Hz), 3.12(dd, 1H, J = 13.3, 4.3 Hz), 2.87 (dd, 1H, J = 13.3, 4.3 Hz). HPLC-MScalculated C₂₄H₂₀F₄N₂O₂ (M + H⁺): 445.2, found: 445.2. 124

¹H NMR (CDCl₃) δ (ppm) 7.37-7.41 (m, 2H), 7.24-7.28 (m, 2H), 7.01-7.18(m, 3H), 5.65 (ovlp d, 1H, J = 4.4 Hz), 4.70-4.76 (m, 1H), 4.54 (pentet,1H, J = 4.0 Hz), 4.09 (ddd, 1H, J = 20.1, 11.6, 4.2 Hz), 3.71-3.90 (m,2H), 3.53- 3.58 (m, 1H), 1.66-1.76 (m, 2H), 1.48-1.63 (m, 4H). HPLC-MScalculated C₂₁H₂₀ClF₂NO₄ (M + H⁺): 424.1, found: 424.1. 125

¹H NMR (CDCl₃) δ (ppm) 7.31-7.40 (m, 6H), 7.25-7.29 (m, 1H), 7.02 (dddd,1H, J = 1.1, 1.1, 1.1, 8.9), 6.71-6.80 (m, 3H), 5.18 (d, 1H, J = 5.3Hz), 4.68 (d, 1H, J = 12.0 Hz), 4.60 (d, 1H, J = 12.0 Hz), 4.38 (q, 1H,J = 4.7 Hz), 3.79 (dd, 1H, J = 10.8, 4.6 Hz), 3.73 (dd, 1H, J = 10.8,3.4 Hz). HPLC- MS calculated C₂₃H₁₇ClF₃NO₃ (M + H⁺): 448.1, found:448.1. 126

¹H NMR (CDCl₃) δ (ppm) 7.64 (d, 1H, J = 2.6 Hz), 7.36 (ddd, 1H, J = 7.9,7.9, 5.8 Hz), 7.31 (d, 1H, J = 8.9 Hz), 7.20 (dd, 1H, J = 8.9, 2.6 Hz),7.08 (d, 1H, J = 7.8 Hz), 6.98-7.06 (m, 2H), 5.16 (d, 1H, J = 5.5 Hz),4.44 (q, 1H, J = 5.8 Hz), 3.18-3.29 (m, 4H), 2.83 (s, 6H), 2.79 (d, 2H,J = 5.8 Hz), 2.55 (t, 4H, J = 4.9 Hz). HPLC- MS calculatedC₂₃H₂₅Cl₂FN₄O₃ (M + H⁺): 495.1, found: 495.1. 127

¹H NMR (CDCl₃) δ (ppm) 7.51-7.56 (m, 4H), 7.37 (ddd, 1H, J = 7.9, 7.9,5.8 Hz), 7.08 (d, 1H, J = 8.0 Hz), 6.99-7.06 (m, 2H), 5.20 (d, 1H, J =5.5 Hz), 4.44 (q, 1H, J = 5.7 Hz), 3.20-3.30 (m, 4H), 2.82-2.84 (m, 8H),2.63 (t, 4H, J = 4.9 Hz). ). HPLC-MS calculated C₂₃H₂₆F₄N₄O₄S (M + H⁺):531.2, found: 531.2. 128

¹H NMR (CDCl₃) δ (ppm) 7.58 (d, 2H, J = 8.8 Hz), 7.52 (d, 2H, J = 7.9Hz), 7.34 (ddd, 1H, J = 7.9, 7.9, 5.8 Hz), 7.09 (d, 1H, J = 7.8 Hz),6.99-7.05 (m, 2H), 5.27 (d, 1H, J = 5.0 Hz), 4.42 (ddd, 1H, J = 7.3,5.1, 5.1 Hz), 2.66-2.77 (m, 2H), 2.47-2.50 (m, 4H), 1.51- 1.65 (m, 4H),1.44-1.48 (m, 2H). HPLC-MS calculated C₂₂H₂₂F₄N₂O₂ (M + H⁺): 423.2,found: 423.2. 129

¹H NMR (CDCl₃) δ (ppm) 7.32-7.37 (m, 3H), 7.21-7.25 (m, 2H), 7.09 (d,1H, J = 7.8 Hz), 6.98-7.05 (m, 2H), 5.19 (d, 1H, J = 5.4 Hz), 4.79 (s,1H), 4.43-4.47 (m, 2H), 4.29 (d, 1H, J = 9.3 Hz), 1.29 (s, 9H). HPLC-MScalculated C₂₁H₂₂ClFN₂O₄ (M + H⁺): 421.1, found: 421.1. 130

¹H NMR (CDCl₃) δ (ppm) 7.50-7.55 (m, 4H), 7.31-7.39 (m, 6H), 7.00-7.07(m, 2H), 6.94 (dt, 1H, J = 9.2, 2.0 Hz), 5.30 (d, 1H, J = 5.1 Hz), 4.69(d, 1H, J = 11.9 Hz), 4.60 (d, 1H, J = 12.0 Hz), 4.43 (q, 1H, J = 4.6Hz), 3.81 (dd, 1H, J = 10.9, 4.4 Hz), 3.75 (dd, 1H, J = 10.9, 3.4 Hz).HPLC-MS calculated C₂₄H₁₉F₄NO₃ (M + H⁺): 446.1, found: 446.1. 131

¹H NMR (acetone-d₆) δ (ppm) 7.51-7.55 (m, 2H), 7.43 (ddd, 1H, J = 7.9,7.9, 5.9), 7.25-7.32 (m, 4H), 7.05-7.10 (m, 1H), 5.88 (d, 1H, J = 6.3Hz), 5.51 (d, 1H, J = 5.7 Hz), 4.51 (q, 1H, J = 5.7 Hz), 3.35 (br s,1H), 2.80-2.97 (m, 4H), 2.19- 2.32 (m, 2H), 1.81 (t, 2H, J = 14.4 Hz),1.55 (dddd, 1H, J = 11.4, 11.4, 11.4, 3.9 Hz), 1.39-149 (m, 10H). HPLC-MS calculated C₂₆H₃₁ClFN₃O₄ (M + H⁺): 504.2, found: 504.2. 132

¹H NMR (CDCl₃) δ (ppm) 7.57-7.59 (m, 2H), 7.47-7.52 (m, 2H), 7.31-7.35(m, 2H), 7.23-7.27 (m, 2H), 6.85-6.91 (m, 4H), 5.26 (dd, 1H, J = 5.6,2.0 Hz), 4.41 (q, 1H, J = 6.1 Hz), 3.97-4.05 (m, 1H), 3.85- 3.91 (m,1H), 3.71-3.78 (m, 1H), 2.74-2.83 (m, 2H), 2.38- 2.66 (m, 10H),1.94-2.02 (m, 1H), 1.80-1.91 (m, 2H), 1.48 (dddd, 1H, J = 12.0, 8.1,8.1, 8.1 Hz). HPLC-MS calculated C₃₂H₃₃ClF₃N₃O₄ (M + H⁺): 616.2, found:616.2. 133

¹H NMR (CDCl₃) δ (ppm) 7.39-7.42 (m, 1H), 7.33-7.37 (m, 2H), 7.25-7.31(m, 3H), 7.20 (dd, 1H, J = 8.8, 1.5 Hz), 5.40 (ovlp d, 1H, J = 4.9 Hz),4.65-4.71 (m, 1H), 4.43-4.47 (m, 1H), 4.02-4.10 (m, 1H), 3.75-3.92 (m,2H), 3.52-3.59 (m, 1H), 1.70-1.82 (m, 2H), 1.51-1.62 (m, 4H). HPLC-MScalculated C₂₂H₂₀ClF₄NO₄ (M + H⁺): 474.1, found: 474.1. 134

¹H NMR (CDCl₃) δ (ppm) 7.32-7.37 (m, 3H), 7.22-7.42 (m, 2H), 7.09 (d,1H, J = 7.8 Hz), 6.98-7.05 (m, 2H), 5.19 (d, 1H, J = 5.2 Hz), 4.73 (d,1H, J = 7.9 Hz), 4.46-4.51 (m, 2H), 4.31-4.36 (m, 1H), 3.41- 3.50 (m,1H), 1.92 (d, 1H, J = 9.7 Hz), 1.83 (d, 1H, J = 10.2 Hz), 1.67-1.72 (m,2H), 1.58-1.59 (m, 1H), 1.26- 1.38 (m, 2H), 1.03-1.19 (m, 3H). HPLC-MScalculated C₂₃H₂₄ClFN₂O₄ (M + H⁺): 447.1, found: 447.1. 136

¹H NMR (CDCl₃) δ (ppm) 7.54 (s, 4H), 7.30-7.38 (m, 6H), 7.00-7.06 (m,2H), 6.92 (dt, 1H, J = 9.1, 2.0), 5.28 (d, 1H, J = 4.9 Hz), 4.68 (d, 1H,J = 12.0 Hz), 4.60 (d, 1H, J = 12.0 Hz), 4.43 (q, 1H, J = 4.4 Hz), 3.81(dd, 1H, J = 10.9, 4.3 Hz), 3.75 (dd, 1H, J = 10.9, 3.3 Hz). HPLC-MScalculated C₂₄H₁₉FN₂O₃ (M + H⁺): 403.1, found: 403.1. 137

¹H NMR (CDCl₃) δ (ppm) 7.39 (s, 1H), 7.24-7.32 (m, 6H), 6.86-6.93 (m,4H), 5.43 (d, 1H, J = 6.1 Hz), 4.39 (ddd, 1H, J = 6.0, 3.0, 3.0 Hz),4.07- 4.12 (m, 1H), 3.83 (ddd, 1H, J = 12.7, 7.7, 2.8 Hz), 2.74 (dd, 1H,J = 7.7, 5.2 Hz). HPLC- MS calculated C₂₃H₁₆ClF₄NO₄ (M + H⁺): 482.1,found: 482.1. 138

¹H NMR (acetone-d₆) δ (ppm) 7.74 (d, 2H, J = 8.7 Hz), 7.63 (d, 2H, J =8.7 Hz), 7.45 (ddd, 1H, J = 8.3, 8.3, 6.2 Hz), 7.37- 7.41 (m, 2H),7.26-7.31 (m, 2H), 7.04-7.14 (m, 3H), 5.67 (d, 1H, J = 5.0), 4.66 (d,2H, J = 1.7), 4.62 (ddd, 1H, J = 5.0, 3.7, 3.7 Hz), 3.95 (d, 1H, J = 3.7Hz). HPLC-MS calculated C₂₄H₁₈F₅NO₃ (M + H⁺): 464.1, found: 464.1. 139

¹H NMR (acetone-d₆) δ (ppm) 7.53 (m, 2H), 7.44 (ddd, 1H, J = 7.9, 7.9,5.9 Hz), 7.27-7.35 (m, 4H), 7.09 (m, 1H), 5.55 (d, 1H, J = 5.7 Hz), 4.57(app q, 1H, J = 5.7 Hz), 4.06 (q, 2H, J = 7.1 Hz), 3.35-3.46 (m, 4H),2.96 (dd, 1H, J = 13.5, 6.2 Hz), 2.88 (dd, 1H, J = 13.5, 5.5 Hz), 2.54(t, 4H, J = 10.1 Hz), 1.20 (t, 3H, J = 7.1 Hz). HPLC-MS calculatedC₂₃H₂₅ClF₂N₃O₄ (M + H⁺): 462.2, found: 462.2. 140

¹H NMR (acetone-d₆) δ (ppm) 7.62 (s, 1H), 7.60 (d, 1H, J = 7.5 Hz), 7.55(d, 1H, J = 7.8 Hz), 7.50 (t, 1H, J = 7.6 Hz), 7.37-7.41 (m, 2H),7.15-7.19 (m, 2H), 7.12 (d, 2H, J = 8.0 Hz), 7.01 (d, 2H, J = 7.9 Hz),5.56 (d, 1H, J = 5.3 Hz), 4.45-4.52 (m, 3H), 3.75-3.81 (m, 2H), 2.18 (s,3H). HPLC-MS calculated C₂₅H₂₁ClF₃NO₃ (M + H⁺): 476.1, found: 476.1. 141

¹H NMR (acetone-d₆) 400 MHz δ (ppm) 8.90 (d, J = 1.4 Hz, 1H), 8.06 (d, J= 1.4 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.67-7.60 (m, 2H)7.43 (m, 2H), 7.18 (m, 2H), 5.78 (d, J = 5.3 Hz, 1H), 4.71 (ddd, J =6.6, 5.9, 5.3 Hz, 1H), 3.64-3.54 (m, 4H), 2.96 (dd, J = 13.3, 6.8 Hz,1H), 2.87 (dd, J = 13.3, 5.2 Hz, 1H). 2.56-2.54 (m, 4H); HPLC-MScalculated C₂₅H₂₂ClF₃N₄O₄ (M + H⁺) 535.1, found 535.1. 142

¹H NMR (acetone-d₆) δ (ppm) 8.47 (s, 1H), 7.86-7.88 (m, 3H), 7.78 (d,1H, J = 7.7 Hz), 7.69 (d, 1H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.7 Hz),7.41-7.45 (m, 4H), 7.33 (t, 1H, J = 7.4 Hz), 7.26-7.29 (m, 2H), 5.81 (d,1H, J = 5.3 Hz), 5.13-5.20 (m, 2H), 5.06 (q, 1H, J = 5.4 Hz). HPLC-MScalculated C₂₅H₁₈ClF₃N₄O₂ (M + H⁺): 499.1, found: 499.1. 143

¹H NMR (acetone-d₆) δ (ppm) 8.6.5 (s, 1H), 7.87 (s, 1H), 7.79 (d, 1H, J= 7.7 Hz), 7.70 (d, 1H, J = 7.8 Hz), 7.65 (t, 1H, J = 7.7 Hz), 7.45-7.48(m, 2H), 7.29-7.31 (m, 2H), 5.82 (d, 1H, J = 5.3 Hz), 5.22 (s, 1H), 5.21(s, 1H), 5.09 (q, 1H, J = 5.2 Hz), 4.33 (q, 2H, J = 7.1 Hz), 1.32 (t,3H, J = 7.1 Hz). HPLC-MS calculated C₂₂H₁₈ClF₃N₄O₄ (M + H⁺): 495.1,found: 495.1. 144

¹H NMR (acetone-d₆) δ (ppm) 8.64 (s, 1H), 7.87 (s, 1H), 7.79 (d, 1H, J =7.7 Hz), 7.70 (d, 1H, J = 7.8 Hz), 7.65 (t, 1H, J = 7.7 Hz), 7.50-7.54(m, 2H), 7.43-7.45 (m, 2H), 7.27-7.29 (m, 2H), 6.99 (tt, 1H, J = 9.2,2.3 Hz), 5.81 (d, 1H, J = 5.4 Hz), 5.17-5.23 (m, 2H), 5.06 (q, 1H, J =5.5 Hz). HPLC-MS calculated C₂₅H₁₆ClF₅N₄O₂ (M + H⁺): 535.1, found:535.1. 145

¹H NMR (CD₃CN) δ (ppm) 7.86 (s, 1H), 7.71 (s, 1H), 7.61-7.66 (m, 2H),7.55 (t, 1H, J = 7.7 Hz), 7.25-7.31 (m, 4H), 5.63 (br s, 1H), 5.44 (d,1H, J = 5.7 Hz), 4.81-4.89 (m, 3H), 4.30 (d, 1H, J = 6.3 Hz), 2.82 (s,3H). HPLC-MS calculated C₂₁H₁₉ClF₃N₅O₄S (M + H⁺): 530.1, found: 530.1.146

HPLC-MS calculated for C₂₄H₁₇ClF₃N₃O₂ (M + H⁺) 472.1, found 472.1. 147

HPLC-MS calculated for C₃₀H₂₁ClF₆N₂O₂ (M + H⁺) 591.1, found 591.1. 148

HPLC-MS C₂₈H₂₃ClF₃N₃O₃ (M + H⁺) 542.1, found 542.1. 150

¹H NMR (CDCl₃, 400 MHz) δ 8.08 (d, 1H), 7.60~7.65 (m, 2H), 7.58 (s, 1H),7.53 (d, 2H), 7.40 (d, 2H), 7.04 (d, 2H), 6.83 (d, 1H), 5.43 (dd, 1H),4.83 (t, 1H), 4.21 (dd, 1H); HPLC-MS calculated for C₂₁H₁₄ClF₃N₂O₃ (M +H⁺) 435.1, found 435.1. 152

¹H NMR (CDCl₃, 400 MHz) δ 7.45~7.58 (m, 4H), 7.29 (d, 2H), 7.23 (d, 2H),6.87 (m, 4H), 5.34 (dd, 1H), 4.82 (br, 1H), 4.01 (t, 1H), 3.35 (dd, 1H);HPLC-MS calculated for C₂₂H₁₆ClF₃N₂O₂ (M + H⁺) 433.1, found 433.1. 154

¹H NMR (CDCl₃, 400 MHz) δ 7.51 (m, 2H), 7.44 (m, 2H), 7.34 (d, 2H), 7.23(m, 4H), 6.87 (m, 6H), 5.17 (dd, 1H), 4.53 (d, 1H), 4.37 (d, 1H), 3.79(s, 3H), 3.76 (t, 1H), 3.07 (dd, 1H); HPLC-MS calculated forC₃₀H₂₄ClF₃N₂O₃ (M + H⁺) 553.1, found 553.1. 156

¹H NMR (CDCl₃, 400 MHz) δ 8.04 (dd, 1H), 7.87 (d, 1H), 7.45~7.57 (m,4H), 7.30 (d, 2H), 7.00 (d, 2H), 6.87 (d, 1H), 5.31 (m, 2H), 4.02 (t,1H), 3.38 (dd, 1H); HPLC- MS calculated for C₂₁H₁₅ClF₃N₃O₂ (M + H⁺)434.1, found 434.1. 157

¹H NMR (CDCl₃, 400 MHz) δ 9.03 (d, 1H), 7.89 (d, 1H), 7.63 (s, 1H),7.52~7.57 (m, 2H), 7.45 (m, 1H), 7.32 (d, 2H), 7.02 (d, 2H), 5.75 (dd,1H), 5.31 (s, 1H), 4.07 (t, 1H), 3.44 (dd, 1H); HPLC-MS calculated forC₂₀H₁₄ClF₃N₄O₂ (M + H⁺) 435.1, found 435.1. 158

HPLC-MS calculated for C₂₉H₂₃ClF₃N₃O₃ (M + H⁺) 554.1, found 554.1. 159

HPLC-MS calculated for C₂₈H₂₂ClF₃N₄O₃ (M + H⁺) 555.1, found 555.1. 160

¹H NMR (CDCl₃, 400 MHz) δ 7.54~7.67 (m, 4H), 7.47 (d, 2H), 7.31 (d, 2H),7.27 (d, 2H), 7.15 (d, 2H), 7.06 (d, 2H), 6.98 (d, 2H), 6.94 (d, 2H),6.92 (d, 2H), 6.91 (d, 2H), 5.22 (dd, 1H), 4.49 (t, 1H), 3.95 (dd, 1H);HPLC- MS calculated for C₃₅H₂₃Cl₂F₃N₄O₂ (M + H⁺) 659.1, found 659.1. 161

¹H NMR (CDCl₃, 400 MHz) δ 8.51 (s, 1H), 8.06 (s, 1H), 7.54 (d, 1H),7.40~7.47 (m, 3H), 7.34 (d, 2H), 7.30 (d, 2H), 7.06 (d, 2H), 6.90 (d,2H), 5.56 (dd, 1H), 4.90 (s, 2H), 3.98 (t, 1H), 3.80 (s, 3H), 3.36 (dd,1H); HPLC-MS calculated for C₂₉H₂₂ClF₃N₆O₂ (M + H⁺) 579.1, found 579.1.162

¹H NMR (CDCl₃, 400 MHz) δ 8.95 (d, 1H), 8.88 (d, 1H), 7.63 (s, 1H), 7.58(d, 1H), 7.52 (d, 1H), 7.46 (t, 1H), 7.32 (d, 2H), 7.01 (d, 2H), 5.67(q, 1H), 5.45 (s, 2H), 4.06 (q, 1H), 3.93 (t, 2H), 3.43 (q, 1H), 3.33(t, 2H); HPLC-MS calculated for C₂₂H₁₉ClF₃N₅O₄S (M + H⁺) 542.1, found542.1. 168

HPLC MS calculated for C₂₉H₂₈ClF₃N₄O₃ (M + H⁺) 573.2, found 573.2. 170

HPLC-MS calculated for C₂₆H₂₃ClF₃N₃O₄ (M + H⁺) 534.1, found 534.1. 171

HPLC-MS calculated for C₂₈H₂₈ClF₃N₄O₃ (M + H⁺) 561.2, found 561.2. 179

HPLC-MS calculated for C₂₈H₂₇ClF₃N₃O₃ (M + H⁺) 546.2, found 546.2. 180

HPLC-MS calculated for C₂₉H₃₀ClF₃N₄O₂ (M + H⁺) 559.2, found 559.2. 182

HPLC-MS calculated for C₂₅H₂₃ClF₃N₃O₂ (M + H⁺) 490.1, found 490.1. 183

HPLC-MS calculated for C₂₉H₂₉ClF₃N₃O₂ (M + H⁺) 544.2, found 544.2. 186

HPLC-MS calculated for C₂₉H₂₁Cl₂F₃N₂O₂ (M + H⁺) 557.1, found 557.1. 187

HPLC-MS calculated for C₂₉H₂₂ClF₃N₂O₂ (M + H⁺) 523.1, found 523.1. 188

HPLC-MS calculated for C₃₀H₂₄ClF₃N₂O₃ (M + H⁺) 553.1, found 553.1. 189

HPLC-MS calculated for C₂₇H₂₁ClFN₅O₂ (M + H⁺): 502.1.0, found: 502.1.501.94 191

HPLC-MS calculated for C₂₈H₂₅ClF₃N₃O₄ (M + H⁺) 560.1, found 560.1. 192

HPLC-MS calculated for C₂₉H₃₀ClF₃N₄O₄S (M + H⁺) 623.2, found 623.2. 193

HPLC-MS calculated for C₃₀H₃₁ClF₃N₃O₃ (M + H⁺) 574.2, found 574.2. 195

HPLC-MS calculated for C₂₇H₂₆ClF₃N₄O₃ (M + H⁺) 547.2, found 547.2. 196

HPLC-MS calculated for C₂₉H₂₈ClF₃N₄O₄ (M + H⁺) 589.2, found 589.2. 197

HPLC-MS calculated for C₂₅H₂₃ClF₃N₃O₄S (M + H⁺) 554.1, found 554.1. 198

HPLC-MS calculated for C₂₈H₂₁ClF₃N₃O₂ (M + H⁺) 524.1, found 524.1. 199

HPLC-MS calculated for C₂₈H₂₁ClF₃N₃O₂ (M + H⁺) 524.1, found 524.1. 200

HPLC-MS calculated for C₂₈H₂₁ClF₃N₃O₂ (M + H⁺) 524.1, found 524.1. 202

¹H NMR (CDCl₃, 400 MHz) δ 7.57 (m, 2H), 7.49 (m, 2H), 7.30 (d, 2H), 7.24(d, 2H), 6.87 (m, 4H), 5.26 (dd, 1H), 3.97 (t, 1H), 3.67 (q, 2H), 3.50(m, 2H), 3.26 (dd, 1H), 3.20 (t, 1H), 1.75 (m, 2H); HPLC-MS calculatedfor C₂₅H₂₂ClF₃N₂O₃ (M + H⁺) 491.1, found 491.1. 204

¹H NMR (CDCl₃, 400 MHz) δ 7.60 (m, 1H), 7.51 (m, 3H), 7.27 (d, 2H), 7.15(d, 2H), 6.88 (m, 4H), 6.65 (br, 1H), 5.40 (dd, 1H), 4.21 (t, 1H), 3.63(dd, 1H); HPLC-MS calculated for C₂₃H₁₆ClF₃N₄O (M + H⁺) 457.1, found457.1. 205

HPLC-MS calculated for C₂₉H₂₉ClF₃N₃O₃ (M + H⁺) 560.2, found 560.2. 206

HPLC-MS calculated for C₂₉H₂₉ClF₃N₃O₃ (M + H⁺) 560.2, found 560.2. 207

HPLC-MS calculated for C₂₅H₂₀ClF₃N₄O₂ (M + H⁺) 501.1, found 501.1. 209

HPLC-MS calculated for C₂₆H₂₂ClF₃N₄O₃S (M + H⁺) 563.1, found 563.1. 210

HPLC-MS calculated for C₂₉H₂₉ClF₃N₃O₃ (M + H⁺) 560.2, found 560.2. 211

HPLC-MS calculated for C₂₆H₂₂ClF₃N₄O₂ (M + H⁺) 515.1, found 515.1. 212

HPLC-MS calculated for C₂₉H₂₇ClF₃N₅O₂ (M + H⁺) 570.2, found 570.2. 213

HPLC-MS calculated for C₃₀H₂₉ClF₃N₅O₂ (M + H⁺) 584.2, found 584.2. 214

HPLC-MS calculated for C₂₇H₂₄ClF₃N₄O₃S (M + H⁺) 577.1, found 577.1. 215

¹H NMR (CDCl₃) δ (ppm) 7.41-7.32 (m, 4H), 7.31-7.23 (m, 5H), 6.92-6.87(m, 4H), 5.24 (dd, J = 7.4, 4.6 Hz, 1H), 2.82-2.78 (m, 1H), 2.71-2.58(m, 2H), 2.10-2.01 (m, 1H). HPLC-MS calculated C₂₂H₁₈ClNO₂ (M + H⁺):364.11, found: 364.10. 216

¹H NMR (CDCl₃) δ (ppm) 9.13 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 1.2 Hz,1H), 7.53-7.49 (m, 2H), 7.46-7.31 (m, 4H), 7.08-7.02 (m, 2H), 5.74 (dd,J = 8.2, 3.8 Hz, 1H), 2.91-2.79 (m, 1H), 2.78-2.63 (m, 2H), 2.11-2.00(m, 1H). HPLC-MS calculated C₂₁H₁₅ClF₃N₃O₂ (M + H⁺): 434.08, found:434.10. 217

¹H NMR (CDCl₃) δ (ppm) 7.63-7.38 (m, 2H), 7.32-7.27 (m, 2H), 6.95-6.73(m, 7H), 5.21 (dd, J = 7.4, 4.6 Hz, 1H), 3.81 (s, 3H), 2.87-2.73 (m,1H), 2.72-2.60 (m, 2H), 2.10- 1.99 (m, 1H). HPLC-MS calculatedC₂₃H₂₀ClNO₃ (M + H⁺): 394.12, found: 394.10. 218

¹H NMR (CDCl₃) δ (ppm) 9.11 (d, J = 1.2 Hz), 7.99 (d, J = 1.6 Hz, 1H),7.37-7.31 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.07-7.02 (m, 2H),6.81-6.72 (m, 3H), 5.68 (dd, J = 8.2, 3.8 Hz, 1H), 3.77 (s, 3H), 2.89-2.74 (m, 1H), 2.72-2.57 (m, 2H), 2.10-1.99 (m, 1H). HPLC-MS calculatedC₂₁H₁₈ClN₃O₃ (M + H⁺): 396.11, found: 396.10. 219

HPLC-MS calculated for C₂₃H₁₇ClF₃NO₃S (M + H⁺) 480.06, found 480.06. 220

¹H NMR (CDCl₃) δ (ppm) 7.84-7.75 (m, 4H), 7.67-7.61 (m, 2H), 7.59-7.41(m, 2H), 7.24 (t, J = 7.6 Hz, 1H), 6.82- 6.77 (m, 1H), 6.77-6.72 (m,1H), 6.70-6.66 (m, 1H), 5.21 (dd, J = 7.6, 4.0 Hz, 1H), 3.75 (s, 3H),2.82-2.69 (m, 1H), 2.69-2.54 (m, 2H), 2.04-1.96 (m, 1H). HPLC-MScalculated for C₂₃H₂₀ClNO₄S (M + H⁺) 442.08, found 442.10. 221

¹H NMR (CDCl₃) δ 7.60-7.50 (m, 1H), 7.49-7.37 (m, 3H), 7.34-7.28 (m,2H), 7.27-7.21 (m, 2H), 6.91-6.67 (m, 4H), 5.28 (dd, J = 6.8, 5.6 Hz,1H), 2.84-2.59 (m, 3H), 2.07-1.94 (m, 1H). HPLC-MS calculated forC₂₃H₁₇ClF₃NO₂ (M + H⁺) 432.09, found 432.10. 223

¹H NMR (CDCl₃) δ 7.58-7.32 (m, 2H), 7.27-7.16 (m, 3H), 6.88-6.79 (m,4H), 6.77-6.66 (m, 3H), 5.15 (dd, J = 8.0, 3.2 Hz, 1H), 2.82-2.54 (m,3H), 2.04-1.92 (m, 1H). HPLC- MS calculated for C₂₂H₁₈ClNO₃ (M + H⁺)380.10, found 380.10. 224

¹H NMR (CDCl₃) δ 7.62-7.36 (m, 2H), 7.30-7.23 (m, 3H), 6.93-6.71 (m,7H), 5.19 (dd, J = 7.4, 4.6 Hz, 1H), 4.11-4.00 (m, 2H), 4.00-3.94 (m,2H), 2.86-2.72 (m, 1H), 2.71-2.58 (m, 2H), 2.10-1.90 (m, 2H). HPLC-MScalculated for C₂₄H₂₂ClNO₄ (M + H⁺) 424.13, found 424.10. 225

HPLC-MS calculated for C₂₄H₂₂ClNO₅S (M + H⁺) 472.09, found 472.10. 226

HPLC-MS calculated for C₂₀H₁₆ClN₃O₃ (M + H⁺) 382.09, found 382.10 227

¹H NMR (CDCl₃) 7.60-7.22 (m, 5H), 6.98-6.68 (m, 7H), 5.20 (dd, J = 7.2,4.8 Hz, 1H), 4.73 (s, 2H), 2.83-2.72 (m, 1H), 2.71-2.58 (m, 2H), 2.06-1.97 (m, 1H). HPLC-MS calculated for C₂₄H₁₉ClN₂O₃ (M + H⁺) 419.11, found419.10. 229

HPLC-MS calculated for C₂₆H₂₁ClF₃NO₂ (M + H⁺) 472.12, found 472.10. 230

HPLC-MS calculated for C₂₆H₂₁ClF₃NO₂ (M + H⁺) 472.12, found 472.10. 231

HPLC-MS calculated for C₂₉H₂₅ClF₃NO₂ (M + 2) 513.15, found 513.10. 232

HPLC-MS calculated for C₂₅H₂₂ClN₅O₃ (M + H⁺) 476.14, found 476.10. 233

HPLC-MS calculated for C₂₅H₂₂ClN₅O₃ (M + H⁺) 476.14, found 476.10. 234

¹H NMR (CDCl₃) δ 7.51-7.46 (m, 1H), 7.44-7.37 (m, 2H), 7.36-7.30 (m,3H), 7.21-7.16 (m, 2H), 6.87-6.78 (m, 4H), 5.21 (dd, J = 10.5, 2.0 Hz,1H), 3.85-3.68 (m, 2H), 2.97-2.85 (m, 1H), 2.45-2.32 (m, 1H), 2.26-2.15(m, 2H), 2.10-1.98 (m, 1H), 1.80-1.69 (m, 1H). HPLC-MS calculated forC₂₅H₂₁ClF₃NO₃ (M + H⁺) 476.12, found 476.10. 235

¹H NMR (CDCl₃) δ 7.46-7.40 (m, 1H), 7.39-7.29 (m, 3H), 7.20-7.11 (m,4H), 6.82-6.75 (m, 4H), 5.17 (dd, J = 11.5, 8.3 Hz, 1H), 3.87-3.71 (m,2H), 2.92-2.73 (m, 2H), 2.16-2.01 (m, 2H), 1.86-1.76 (m, 1H), 1.75-1.62(m, 1H). HPLC-MS calculated for C₂₅H₂₁ClF₃NO₃ (M + H⁺) 476.12, found476.10. 236

HPLC-MS calculated for C₂₄H₂₄ClNO₃ (M + H⁺) 410.14, found 410.10. 237

¹H NMR (CDCl₃) δ 7.60-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.43-7.35 (m,3H), 7.28-7.22 (m, 2H), 6.93-6.83 (m, 4H), 5.24 (dd, J = 10.5, 3.0 Hz,1H), 3.70 (t, J = 7.2 Hz, 2H), 2.87- 2.75 (m, 1H), 2.45-2.33 (m, 1H),2.26-2.16 (m, 1H), 2.11- 1.98 (m, 1H), 1.87 (s, br, 1H), 1.75-1.58 (m,3H). HPLC-MS calculated for C₂₆H₂₃ClF₃NO₃ (M + H⁺) 490.13, found 490.10.238

¹H NMR (CDCl₃) δ 7.51-7.46 (m, 1H), 7.45-7.34 (m, 3H), 7.26-7.24 (m,1H), 7.24-7.21 (m, 2H), 7.21-7.19 (m, 1H), 6.89-6.81 (m, 4H), 5.20 (dd,J = 11.3, 8.3 Hz, 1H), 3.73 (t, J = 7.5 Hz, 2H), 2.89-2.71 (m, 2H),2.18-2.06 (m, 1H), 1.75 (s, br, 1H), 1.74-1.62 (m, 4H). HPLC-MScalculated for C₂₆H₂₃ClF₃NO₃ (M + H⁺) 490.13, found 490.10. 239

¹H NMR (CDCl₃) δ 7.44-7.38 (m, 2H), 7.29-7.20 (m, 3H), 6.83-6.77 (m,2H), 6.75-6.72 (m, 1H), 5.20 (dd, J = 10.0, 5.5 Hz, 1H), 3.77 (s, 3H),2.84- 2.73 (m, 1H), 2.72-2.56 (m, 2H), 2.07-1.96 (m, 1H). HPLC-MScalculated for C₁₇H₁₆ClNO₂ (M + H⁺) 302.09, found 302.10. 240

¹H NMR (CDCl₃) δ 8.98 (d, J = 5.0 Hz, 1H), 7.55 (dd, J = 11.0, 5.5 Hz,1H), 7.41- 7.35 (m, 3H), 7.25-7.20 (m, 2H), 7.17 (dd, J = 11.0, 1.0 Hz,1H), 7.12 (ddd, J = 10.5, 3.0, 1.0 Hz, 1H), 7.09 (d, J = 9.5 Hz, 1H),7.06-7.02 (m, 1H), 5.23 (dd, J = 10.0, 6.0 Hz, 1H), 2.80-2.52 (m, 3H),2.11-2.02 (m, 1H). HPLC-MS calculated for C₂₀H₁₆ClN₃O₂ (M + H⁺) 366.09,found 366.00. 241

¹H NMR (CDCl₃) δ 8.39 (s, 1H), 8.28 (d, J = 3.0 Hz, 1H), 8.05 (dd, J =3.0, 1.5 Hz, 1H), 7.41-7.33 (m, 3H), 7.22 (d, J = 11.0 Hz, 2H),7.12-7.04 (m, 2H), 7.00-6.96 (m, 1H), 5.23 (dd, J = 10.0, 5.5 Hz, 1H),2.79-2.56 (m, 3H), 2.10-2.02 (m, 1H). HPLC-MS calculated forC₂₀H₁₆ClN₃O₂ (M + H⁺) 366.09, found 366.00. 242

¹H NMR (CDCl₃) δ 7.39 (d, J = 11.0 Hz, 2H), 7.25-7.17 (m, 3H), 6.83-6.77(m, 2H), 6.75- 6.72 (m, 1H), 5.17 (dd, J = 10.0, 6.0 Hz, 1H), 4.08- 3.96(m, 2H), 3.94 (t, J = 5.5 Hz, 2H), 2.82-2.71 (m, 1H), 2.70-2.55 (m, 2H),2.05-1.93 (m, 1H), 1.76 (s, br, 1H). HPLC-MS calculated for C₁₈H₁₈ClNO₃(M + H⁺) 332.10, found 332.00. 245

¹H NMR (CDCl₃) δ 7.24-7.13 (m, 5H), 6.85 (d, J = 8.5 Hz, 1H), 6.79 (t, J= 4.0 Hz), 6.75 (ddd, J = 10.5, 3.0, 1.0 Hz, 1H), 5.01 (dd, J = 12.5,8.0 Hz, 1H), 4.20 (dd, J = 12.5, 8.0 Hz, 1H), 3.88 (s, 3H), 3.75 (t, J =12.5 Hz, 1H), 3.68 (s, 3H), HPLC-MS calculated for C₁₇H₁₇ClN₂O₅S (M +H⁺) 397.05, found 397.10. 246

¹H NMR (CDCl₃) δ 7.29 (t, J = 10.0 Hz, 1H), 7.23 (d, J = 11.5 Hz, 2H),7.10 (d, J = 11.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 1H), 6.89 (d, J = 3.0Hz, 1H), 6.85 (ddd, J = 10.5, 3.0, 1.0 Hz, 1H), 5.15 (t, J = 7.5 Hz,1H), 4.75-4.61 (m, 1H), 4.06-3.94 (m, 1H) 3.78 (s, 3H), 3.46 (ddd, J =15.3, 9.0, 6.5 Hz, 1H). HPLC-MS calculated for C₁₅H₁₅ClN₂O₃S (M + 2)339.05, found 339.00. 247

¹H NMR (CDCl₃) δ 7.37 (d, J = 11.5 Hz, 2H), 7.31 (t, J = 10.0, 1H), 7.21(d, J = 11.5 Hz, 2H), 6.93 (d, J = 10.0 Hz, 1H), 6.87 (ddd, J = 10.0,3.0, 1.0 Hz, 1H), 6.82-6.78 (m, 1H), 5.21 (dd, J = 9.5, 6.0 Hz, 1H),4.73 (s, 2H), 2.80-2.70 (m, 1H), 2.70-2.53 (m, 2H), 2.03-1.92 (m, 1H).HPLC-MS calculated for C₁₈H₁₅ClN₂O₂ (M + H⁺) 327.08, found 327.10. 248

HPLC-MS calculated for C₁₆H₁₅ClN₂O₅S (M + H⁺) 383.04, found 383.10. 249

HPLC-MS calculated for C₁₄H₁₃ClN₂O₃S (M + H⁺) 325.03, found 325.00. 250

¹H NMR (CDCl₃) δ 8.83 (s, br, 1H), 8.41 (s, br, 1H), 8.36 (s, br, 1H),8.30 (s, br, 2H), 8.05 (s, br, 1H), 7.42 (t, J = 10.0 Hz, 1H), 7.35-7.24(m, 6H), 7.15 (dd, J = 10.0, 2.5 Hz, 1H), 5.32 (dd, J = 11.0, 8.5 Hz,1H), 4.55 (dd, J = 13.0, 8.5 Hz, 1H), 4.08 (t, J = 12.5 Hz, 1H). HPLC-MScalculated for C₂₂H₁₇ClN₆O₃S (M + H⁺) 481.08, found 481.10. 251

HPLC-MS calculated for C₁₈H₁₅ClN₄O₃S (M + H⁺) 403.06, found 403.00. 252

HPLC-MS calculated for C₁₈H₂₂ClN₃O₅S₂ [(M- 2PMB) + H⁺] 460.07, found460.10. 253

¹H NMR (CDCl₃) δ 8.41 (s, br, 1H), 8.29 (d, J = 3.5 Hz, 1H), 8.05 (dd, J= 5.0, 2.0 Hz, 1H), 7.41 (t, J = 10.0 Hz, 1H), 7.30-7.22 (m, 3H),7.20-7.17 (m, 1H), 7.16-7.10 (m, 3H), 5.16 (dd, J = 10.5, 8.0 Hz, 1H),3.88 (dd, J = 12.0, 8.5 Hz, 1H), 3.47-3.39 (m, 1H), 3.34-3.14 (m, 4H),2.93 (s, 3H), 2.31- 2.20 (m, 2H). HPLC-MS calculated for C₂₂H₂₃ClN₄O₅S₂(M + H⁺) 523.08, found 523.10. 255

¹H NMR (CDCl₃) δ 7.34 (t, J = 10.0 Hz, 1H), 7.31-7.27 (m, 2H), 7.23-7.19(m, 2H), 7.10 (d, J = 9.5 Hz, 1H), 7.07-7.04 (m, 1H), 6.94 (ddd, J =10.0, 3.0, 1.0 Hz, 1H), 5.19 (dd, J = 10.5, 8.5 Hz, 1H), 4.75 (s, 2H),4.16 (s, 2H), 4.02 (dd, J = 12.5, 8.5 Hz, 1H), 3.47 (dd, J = 12.5, 10.5Hz, 1H). HPLC- MS calculated for C₁₈H₁₅ClN₄O₃S (M + H⁺) 403.06, found402.90. 256

¹H NMR (CDCl₃) δ 8.82 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 3.0 Hz, 1H),8.32 (dd, J = 3.0, 2.0 Hz, 1H), 7.33-7.27 (m, 4H), 7.27-7.23 (m, 1H),7.00 (d, J = 10.0 Hz, 1H), 6.96-6.93 (m, 1H), 6.85 (ddd, J = 10.0, 3.0,1.0 Hz, 1H), 5.27 (dd, J = 11.5, 8.0 Hz, 1H), 4.50 (dd, J = 13.0, 8.0Hz, 1H), 4.04 (dd, J = 13.0, 11.5 Hz, 1H), 3.77 (s, 3H). HPLC-MScalculated for C₁₉H₁₇ClN₄O₃S (M + H⁺) 417.07, found 417.10. 257

¹H NMR (CDCl₃) δ 9.08 (d, J = 5.5 Hz, 1H), 8.03 (d, J = 11.5 Hz, 1H),7.81 (dd, J = 11.5, 5.5 Hz, 1H), 7.36- 7.29 (m, 4H), 7.28-7.24 (m, 1H),6.99 (d, J = 9.5 Hz, 1H), 6.95-6.91 (m, 1H), 6.86 (ddd, J = 10.5, 3.0,1.0 Hz, 1H), 5.30 (dd, J = 11.5, 8.0 Hz, 1H), 4.75 (dd, J = 13.5, 8.0Hz, 1H), 4.20 (dd, J = 13.5, 11.5 Hz, 1H), 3.77 (s, 3H). HPLC-MScalculated for C₁₉H₁₇ClN₄O₃S (M + H⁺) 417.07, found 417.10. 258

HPLC-MS calculated for C₂₁H₁₉ClN₂O₃S (M + H⁺) 415.08, found 4l5.10. 259

¹H NMR (CDCl₃) δ 7.29-7.23 (m, 3H), 7.22-7.17 (m, 2H), 6.95 (d, J = 9.5Hz, 1H), 6.92- 6.89 (m, 1H), 6.84 (ddd, J = 10.5, 3.0, 1.0 Hz, 1H), 5.17(dd, J = 11.0, 8.5 Hz, 1H), 4.14 (AB, J = 29.5, 22.0 Hz, 2H), 3.97 (dd,J = 12.0, 8.5 Hz, 1H), 3.77 (s, 3H), 3.48 (dd, J = 12.0, 11.0 Hz, 1H).HPLC-MS calculated for C₁₇H₁₆ClN₃O₃S (M + H⁺) 378.06, found 378.10. 260

¹H NMR (CDCl₃) δ ppm) 7.27-7.25 (m, 1H), 7.25-7.22 (m, 2H), 7.16-7.11(m, 2H), 6.92 (d, J = 9.5 Hz, 1H), 6.89- 6.86 (m, 1H), 6.82 (ddd, J =10.0, 3.0, 1.0 Hz, 1H), 5.02 (dd, J = 9.5, 8.5 Hz, 1H), 4.18 (d, J =17.5 Hz, 1H), 3.89 (d, J = 17.5 Hz, 1H), 3.76 (s, 3H), 3.62 (dd, J =11.5, 8.5 Hz, 1H), 3.10 (dd, J = 11.5, 9.5 Hz, 1H), 2.35 (s, 3H), 2.28(s, 3H). (HPLC-MS calculated for C₂₁H₂₂ClN₃O₄S (M + H⁺) 448.10, found448.10. 261

¹H NMR (CDCl₃) δ 7.28-7.26 (m, 1H), 7.26-7.21 (m, 2H), 7.18-7.13 (m,2H), 6.90 (d, J = 10.0 Hz, 1H), 6.87-6.84 (m, 1H), 6.82 (ddd, J = 10.0,3.5, 1.0 Hz, 1H), 6.81 (s, 1H), 5.07 (dd, J = 10.5, 8.5 Hz, 1H), 4.66(dd, J = 20.0, 0.5 Hz, 1H), 4.37 (d, J = 20.0 Hz, 1H), 3.98 (s, 3H),3.88 (dd, J = 12.5 8.5 Hz, 1H), 3.76 (s, 3H), 3.50 (dd, J = 12.5, 10.5Hz, 1H). HPLC- MS calculated for C₂₁H₂₀ClN₃O₆S (M + H⁺) 478.08, found478.10. 262

¹H NMR (CDCl₃) δ 8.76 (s, 1H), 7.27-7.26 (m, 1H), 7.25- 7.21 (m, 2H),7.20-7.15 (m, 2H), 6.94 (d, J = 9.5 Hz, 1H), 6.91-6.88 (m, 1H), 6.82(ddd, J = 10.0, 3.0, 1.0 Hz, 1H), 5.14 (dd, J = 11.0, 8.5 Hz, 1H), 4.72(d, J = 19.5 Hz, 1H), 4.35 (d, J = 19.5 Hz, 1H), 4.03 (dd, J = 12.0, 8.5Hz, 1H), 3.76 (s, 3H), 3.43 (dd, J = 12.0, 11.0, 1H). HPLC-MS calculatedfor C₁₈H₁₇ClN₄O₄S (M + H⁺) 421.07, found 421.10. 263

HPLC-MS calculated for C₂₀H₁₇ClN₂O₃ S (M + H⁺) 401.06, found 401.10. 264

¹H NMR (CDCl₃) δ 8.41 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 3.5 Hz, 1H),8.07 (dd, J = 3.5, 1.5 Hz, 1H), 7.44-7.39 (m, 1H), 7.30-7.27 (m, 1H),7.26-7.23 (m, 2H), 7.21-7.18 (m, 1H), 7.16-7.10 (m, 3H), 5.15 (dd, J =8.5, 8.0 Hz, 1H), 4.73 (s, br, 2H), 3.88 (dd, J = 11.5, 8.5 Hz, 1H),3.45-3.20 (m, 5H), 2.27- 2.18 (m, 2H). HPLC-MS calculated forC₂₁H₂₂ClN₅O₅S₂ (M + H⁺) 524.08, found 524.10. 265

¹H NMR (CDCl₃) δ 8.42 (d, J = 1.5 Hz, 1H), 8.30 (d, J = 3.5 Hz, 1H),8.05 (dd, J = 3.5, 1.5 Hz, 1H), 7.46-7.42 (m, 1H), 7.42-7.38 (m, 2H),7.36-7.27 (m, 6H), 7.27-7.22 (m, 3H), 7.15 (ddd, J = 10.0, 3.0, 1.0 Hz,1H), 5.30 (dd, J = 10.5, 8.0 Hz, 1H), 4.18 (dd, J = 11.5, 8.0 Hz, 1H),3.90 (dd, J = 11.5, 10.5 Hz, 1H). HPLC-MS calculated for C₂₄H₁₉ClN₄O₃S(M + H⁺) 479.09, found 479.10. 266

¹H NMR (CDCl₃) δ 8.42 (d, J = 1.5 Hz, 1H), 8.29 (J = 3.5 Hz, 1H), 8.03(dd, J = 3.5, 1.5 Hz, 1H), 7.43-7.37 (m, 1H), 7.29-7.27 (m, 1H),7.26-7.20 (m, 2H), 7.19-7.10 (m, 4H), 5.08 (dd, J = 9.5, 8.5 Hz, 1H),4.18 (d, J = 17.5 Hz, 1H), 3.89 (d, J = 17.5 Hz, 1H), 3.67 (dd, J =12.0, 8.5 Hz, 1H), 3.15 (dd, J = 12.0, 9.5 Hz, 1H), 2.35 (s, 3H), 2.27(s, 3H). HPLC-MS calculated for C₂₄H₂₂ClN₅O₄S (M + H⁺) 512.11, found512.10. 267

¹H NMR (CDCl₃) δ 7.38-7.32 (m, 2H), 7.31-7.26 (m, 3H), 7.25-7.20 (m,2H), 7.15-7.08 (m, 2H), 7.02 (d, J = 9.5 Hz, 1H), 6.99-6.96 (m, 1H),6.85 (ddd, J = 10.0, 3.0, 1.0 Hz, 1H), 5.24 (dd, J = 10.5, 8.0 Hz, 1H),4.09 (dd, J = 11.5, 8.0 Hz, 1H), 3.83 (dd, J = 11.5, 10.5 MS calculatedfor C₂₁H₁₈ClFN₂O₃S (M + H⁺) 433.07, found 433.10. 268

¹H NMR (CDCl₃) δ 9.13 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H),7.37-7.32 (m, 2H), 7.32-7.26 (m, 1H), 7.08-7.02 (m, 2H), 6.94 (d, J =9.5 Hz, 1H), 6.88-6.80 (m, 2H), 5.69 (dd, J = 10.0, 4.0 Hz, 1H), 4.74(s, 2H), 2.90-2.74 (m, 1H), 2.74-2.60 (m, 2H), 2.11-2.00 (m, 1H).HPLC-MS calculated for C₂₂H₁₇ClN₄O₃ (M + H⁺) 421.10, found 420.90. 273

HPLC-MS calculated for C₂₂H₁₅ClN₂O₃ (M + H⁺): 391.1, found 391.1. 274

¹H NMR (CDCl₃) δ 7.45 (dd, J = 7.6, 1.6 Hz, 1H), 7.33- 7.19 (m, 6H),7.15-7.11 (m, 1H), 7.01-6.99 (m, 1H), 6.89- 6.87 (m, 2H), 6.81 (t, J =1.6 Hz, 1H), 5.34 (dd, J = 8.8, 6.0 Hz, 1H), 4.78 (t, J = 8.4 Hz, 1H),4.20 (dd, J = 8.8, 6.4 Hz, 1H); HPLC-MS calculated for C₂₁H₁₅Cl₂NO₃ (M +H⁺): 400.1, found 400.1 275

¹H NMR (CDCl₃) δ 7.31-7.23 (m, 5H), 6.95-6.93 (m, 1H), 6.86-6.81 (m,6H), 6.87 (m, 4H), 6.87-6.84 (m, 1H), 6.82 (t, J = 2.0 Hz, 1H), 5.32(dd, J = 8.8, 6.4 Hz, 1H), 4.77 (t, J = 8.8 Hz, 1H), 4.20 (dd, J = 8.8,6.0 Hz, 1H), 3.82 (s, 3H); HPLC-MS calculated for C₂₂H₁₈ClNO₄ (M + H⁺):396.1, found 396.1. 277

HPLC-MS calculated for C₂₂H₁₅ClN₂O₃ (M + H⁺): 391.1, found 391.0. 278

HPLC-MS calculated for C₂₀H₁₅ClN₂O₃ (M + H⁺): 367.1, 367.0. 281

HPLC-MS calculated for C₁₈H₁₈ClNO₃ (M + H⁺): 332.1, found 332.1. 282

HPLC-MS calculated for C₁₉H₁₈ClNO₃ (M + H⁺); 344.1, found 344.1. 283

HPLC-MS calculated for C₂₀H₂₃ClN₂O₃ (M + H⁺): 375.1, found 375.1. 284

HPLC-MS calculated for C₁₆H₁₃Cl₂NO₃ (M + H⁺): 329.0, found 329.0. 285

¹H NMR (CDCl₃) δ 7.38-7.34 (m, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.25-7.21(m, 2H), 6.90- 6.85 (m, 2H), 6.82 (t, J = 2.0 Hz, 1H), 5.32 (dd, J =8.8, 6.0 Hz, 1H), 4.78 (t, J = 8.8 Hz, 1H), 4.20 (dd, J = 8.8, 6.0 Hz,1H), 4.21-4.00 (m, 2H), 3.95 (t, J = 4.0 Hz, 2H); HPLC-MS calculated forC₁₇H₁₆ClNO₄ (M + H⁺): 334.1, found 334.0. 286

HPLC-MS calculated for C₁₅H₁₂ClNO₃ (M + H⁺): 290.0, found 290.0. 287

¹H NMR (CDCl₃) δ 7.37-7.34 (2H, m), 7.28 (1H, t, J = 8.0 Hz), 7.24-7.21(2H, m), 6.87- 6.84 (2H, m), 6.79 (1H, t, J = 2.0 Hz), 5.32 (1H, dd, J =6.0, 8.8 Hz), 4.77 (1H, t, J = 8.8 Hz), 4.20 (1H, dd, J = 6.0, 8.8 Hz),3.77 (3H, s); HPLC-MS calculated for C₁₆H₁₄ClNO₃ (M + H⁺) 304.1, found304.1. 292

HPLC-MS calculated for C₂₈H₂₅ClN₄O₅S (M + H⁺): 565.1, found 565.1. 297

HPLC-MS calculated for C₂₂H₂₁ClN₄O₄S (M + H⁺): 473.1, found 473.1. 298

HPLC-MS calculated for C₂₅H₂₂ClN₃O₄S (M + H⁺): 496.1, found 496.1. 299

HPLC-MS calculated for C₂₂H₂₁ClN₄O₄S (M + H⁺): 473.1, found 473.1. 300

HPLC-MS calculated for C₂₃H₂₂ClN₃O₄S (M + H⁺): 472.1, found 472.1. 301

¹H NMR (CDCl₃) δ 8.46-8.42 (m, 2H), 7.53-7.48 (m, 2H), 7.44-7.40 (t, J =8.4 Hz, 1H), 7.30-7.28 (m, 2H), 7.21-7.19 (m, 3H), 7.02-6.99 (m, 2H),5.24 (dd, J = 6.0, 9.6 Hz, 1H), 4.04 (t, J = 9.2 Hz, 1H), 3.93- 3.87 (m,1H), 3.79-3.72 (m, 1H), 3.48 (dd, J = 8.8, 6.0 Hz, 1H), 3.34-3.30 (m,2H), 3.00 (s, 3H); HPLC-MS calculated for C₂₃H₂₂ClN₃O₄S (M + H⁺): 472.1,found 472.1. 302

HPLC-MS calculated for C₂₃H₂₂ClN₃O₄S (M + H⁺): 472.1, found 472.1. 303

HPLC-MS calculated for C₂₂H₂₁ClN₄O₄S (M + H⁺): 473.1, found 473.1. 304

HPLC-MS calculated for C₂₅H₂₅ClN₂O₅S (M + H⁺): 501.1, found 501.1. 305

HPLC-MS calculated for C₂₂H₂₂ClN₅O₄S (M + H⁺): 488.0, found 488.0. 306

HPLC-MS calculated for C₂₂H₂₁ClN₄O₄S (M + H⁺): 473.1, found 473.1. 308

¹H NMR (acetone-d₆) δ 7.50- 7.54 (m, 2H), 7.44 (ddd, 1H, J = 7.9, 7.9,5.9 Hz), 7.34-7.38 (m, 3H), 7.30 (dt, 1H, J = 9.8, 2.5 Hz), 7.07-7.12(m, 1H), 6.94-6.98 (m, 4H), 5.52 (d, 1H, J = 5.9 Hz), 4.55 (q, 1H, J =5.9 Hz), 3.55-3.64 (m, 4H), 2.91 (dd, 1H, J = 13.4, 6.1 Hz), 2.83 (dd,1H, J = 13.4, 6.1 Hz), 2.54 (br s, 4H). HPLC-MS calculated C₂₆H₂₄ClFN₂O₄(M + H⁺): 483.1, found: 483.1. 309

¹H NMR (acetone-d₆) δ 7.89 (s, 1H), 7.82 (d, 1H, J = 7.2 Hz), 7.62-7.69(m, 2H), 7.50- 7.54 (m, 2H), 7.34-7.38 (m, 2H), 6.93-6.97 (m, 4H), 5.66(d, 1H, J = 5.9 Hz), 4.60 (q, 1H, J = 5.5 Hz), 3.53-3.64 (m, 4H), 2.95(dd, 1H, J = 13.3, 6.7 Hz), 2.85 (dd, 1H, J = 13.3, 6.7 Hz), 2.49-2.57(m, 4H). HPLC-MS calculated C₂₇H₂₄ClF₃N₂O₄ (M + H⁺): 533.1, found:533.1. 310

¹H NMR (acetone-d₆) δ 7.50- 7.54 (m, 2H), 7.34-7.38 (m, 2H), 7.30 (t,1H, J = 7.8 Hz), 7.01-7.05 (m, 2H), 6.92-6.97 (m, 4H), 6.87 (ddd, 1H, J= 8.3, 2.4, 1.1 Hz), 5.41 (d, 1H, J = 5.8 Hz), 4.51 (q, 1H, J = 5.8 Hz),3.78 (s, 3H), 3.57- 3.64 (m, 4H), 2.88 (dd, 1H, J = 13.4, 5.8 Hz), 2.80(dd, 1H, J = 13.4, 5.8 Hz), 2.53 (t, 4H, J = 4.5 Hz). HPLC-MS calculatedC₂₇H₂₇ClN₂O₅ (M + H⁺): 495.2, found: 495.2. 312

¹H NMR (acetone-d₆) δ 7.51- 7.55 (m, 2H), 7.27-7.31 (m, 3H), 6.99-7.03(m, 2H), 6.87 (ddd, 1H, J = 8.3, 2.5, 0.9 Hz), 5.4.2 (d, 1H, J = 5.6Hz), 4.49 (q, 1H, J = 5.6 Hz), 4.08 (q, 2H, J = 7.1 Hz), 3.77 (s, 3H),2.76-2.97 (m, 4H), 2.16-2.31 (m, 3H), 1.78-1.86 (m, 2H), 1.57-1.76 (m,2H), 1.21 (t, 3H, J = 7.1 Hz). HPLC-MS calculated C₂₅H₂₉ClN₂O₅ (M + H⁺):473.2, found: 473.2. 313

¹H NMR (acetone-d₆) δ 7.54 (dd, 2H, J = 8.8, 1.4 Hz), 7.27- 7.32 (m,3H), 6.99-7.01 (m, 2H), 6.86-6.89 (m, 1H), 5.43 (t, 1H, J = 5.4 Hz),4.45 (q, 1H, J = 5.4 Hz), 3.77 (s, 3H), 3.34-3.48 (m, 4H), 3.02 (dd, 2H,J = 5.8, 3.3 Hz), 2.75-2.88 (m, 4H), 1.68-1.78 (m, 2H), 1.43 (d, 9H, J =1.4 Hz). HPLC-MS calculated C₂₇H₃₄ClN₃O₅ (M + H⁺): 516.2, found: 516.2.314

¹H NMR (acetone-d₆) δ 8.57 (s, 1H), 7.72 (ddd, 1H, J = 7.8, 1.3, 1.3Hz), 7.64 (ddd, 1H, J = 10.3, 2.6, 1.5 Hz), 7.41- 7.50 (m, 3H),7.25-7.32 (m, 3H), 7.08-7.13 (m, 1H), 6.99- 7.03 (m, 2H), 6.89 (ddd, 1H,J = 8.3, 2.5, 1.0 Hz), 5.58 (d, 1H, J = 5.4 Hz), 5.12-5.13 (m, 2H), 4.95(ddd, 1H, J = 5.5, 5.5, 4.7 Hz), 3.75 (s, 3H). HPLC-MS calculatedC₂₅H₂₀ClFN₄O₃ (M + H⁺): 479.1, found: 479.1. 315

¹H NMR (acetone-d₆) δ 8.49 (s, 1H), 8.25 (dd, 1H, J = 7.7, 1.7 Hz),7.41-7.45 (m, 2H), 7.25-7.35 (m, 4H), 7.10 (d, 1H, J = 7.6 Hz), 7.05(ddd, 1H, J = 7.6, 7.6, 1.1 Hz), 6.97-6.99 (m, 2H), 6.88 (ddd, 1H, J =8.3, 2.4, 1.0 Hz), 5.56 (d, 1H, J = 5.3 Hz), 5.10 (d, 2H, J = 5.1 Hz),4.94 (q, 1H, J = 5.3 Hz), 3.94 (s, 3H), 3.74 (s, 3H). HPLC-MS calculatedC₂₆H₂₃ClN₄O₄ (M + H⁺): 491.1, found: 491.1. 316

¹H NMR (acetone-d₆) δ 8.66 (s, 1H), 7.44-7.47 (m, 2H), 7.27-7.32 (m,3H), 6.99-7.03 (m, 2H), 6.89 (ddd, 1H, J = 8.3, 2.5, 0.9 Hz), 5.59 (d,1H, J = 5.4 Hz), 5.16 (d, 2H, J = 5.3 Hz), 4.97 (q, 1H, J = 5.4 Hz),4.32 (q, 2H, J = 7.1 Hz), 3.77 (s, 3H), 1.32 (t, 3H, J = 7.1 Hz).HPLC-MS calculated C₂₂H₂₁ClN₄O₅ (M + H⁺): 457.1, found: 457.1. 317

¹H NMR (acetone-d₆) δ 7.50- 7.54 (m, 2H), 7.27-7.32 (m, 3H), 7.01-7.04(m, 2H), 6.87 (ddd, 1H, J = 8.3, 2.5, 1.0 Hz), 5.44 (d, 1H, J = 5.8 Hz),4.54 (q, 1H, J = 5.7 Hz), 3.77 (s, 3H), 3.20-3.30 (m, 4H), 2.88- 3.03(m, 4H), 2.66 (t, 4H, J = 4.9 Hz), 1.28 (t, 3H, J = 7.4 Hz). HPLC-MScalculated C₂₃H₂₈ClN₃O₅S (M + H⁺): 494.1, found: 494.1. 318

¹H NMR (acetone-d₆) δ 7.80 (s, 1H), 7.39-7.42 (m, 2H), 7.26-7.31 (m,3H), 6.95-6.96 (m, 1H), 6.92 (d, 1H, J = 7.7 Hz), 6.88 (ddd, 1H, J =8.3, 2.5, 0.8 Hz), 5.48 (d, 1H, J = 5.0 Hz), 4.92-5.02 (m, 2H), 4.85 (q,1H, J = 5.1 Hz), 3.76 (m, 3H), 3.08-3.16 (m, 1H), 1.94-2.01 (m, 2H),1.59-1.72 (m, 5H). HPLC-MS calculated C₂₄H₂₅ClN₄O₃ (M + H⁺): 453.2,found: 453.2. 319

¹H NMR (acetone-d₆) δ 8.37 (s, 1H), 7.81 (t, 1H, J = 2.3 Hz), 7.53-7.56(m, 2H), 7.41- 7.45 (m, 2H), 7.26-7.33 (m, 3H), 6.99-7.01 (m, 2H), 6.87-6.90 (m, 1H), 5.56 (d, 1H, J = 5.5 Hz), 5.09 (d, 2H, J = 5.1 Hz), 4.92(q, 1H, J = 5.4 Hz), 3.75 (s, 3H). HPLC-MS calculated C₂₃H₁₉ClN₄O₃S (M +H⁺): 467.1, found: 467.1. 320

¹H NMR (acetone-d₆) δ 7.78 (s, 1H), 7.39-7.43 (m, 2H), 7.26-7.31 (m,3H), 6.97-6.98 (m, 1H), 6.93 (d, 1H, J = 7.0 Hz), 6.88 (ddd, 1H, J =8.3, 2.5, 0.8 Hz), 5.48 (d, 1H, J = 4.96 Hz), 4.93-5.03 (m, 2H), 4.85(q, 1H, J = 5.0 Hz), 3.77 (s, 3H), 2.51 (d, 2H, J = 6.9 Hz), 1.48-1.63(m, 6H), 1.07- 1.21 (m, 3H), 0.83-0.93 (m, 2H). HPLC-MS calculatedC₂₆H₂₉ClN₄O₃ (M + H⁺): 481.2, found: 481.2. 321

¹H NMR (acetone-d₆) δ 8.61 (s, 1H), 7.43-4.47 (m, 2H), 7.28-7.33 (m,3H), 6.98-7.02 (m, 2H), 6.89 (dd, 1H, J = 8.3, 2.5 Hz), 5.58 (d, 1H, J =5.4 Hz), 5.16-5.17 (m, 2H), 4.97 (q, 1H, J = 4.9 Hz), 3.77 (s, 3H), 2.55(s, 3H). HPLC-MS calculated C₂₁H₁₉ClN₄O₄ (M + H⁺): 427.1, found: 427.1.322

¹H NMR (acetone-d₆) δ 7.80 (s, 1H), 7.39-7.43 (m, 2H), 7.27-7.32 (m,3H), 6.93-6.96 (m, 2H), 6.87-6.90 (m, 1H), 5.47 (d, 1H, J = 5.0 Hz),4.93- 5.02 (m, 2H), 4.83-4.86 (m, 1H), 3.77 (m, 3H), 2.64 (t, 2H, J =7.8 Hz), 1.44-1.55 (m, 3H), 0.87-0.89 (m, 6H). HPLC-MS calculatedC₂₄H₂₇ClN₄O₃ (M + H⁺): 455.2, found: 455.2. 323

HPLC-MS calculated: C₂₅H₂₂ClN₅O₄ (M + H⁺): 492.1, found: 492.1 325

¹H NMR (acetone-d₆) δ 7.43- 7.47 (m, 2H), 7.28-7.33 (m, 3H), 7.04 (t,1H, J = 2.1 Hz), 6.98 (d, 1H, J = 7.7 Hz), 6.91 (ddd, 1H, J = 8.3, 2.6,0.9 Hz), 5.61 (d, 1H, J = 5.0 Hz), 5.32 (dd, 1H, J = 14.6, 5.6, Hz),5.25 (dd, 1H, J = 14.6, 5.6 Hz), 4.99 (ddd, 1H, J = 5.0. 5.0, 4.2 Hz),3.78 (s, 3H), 2.93 (t, 2H, J = 7.6 Hz), 2.50-2.57 (m, 2H), 2.37 (br s,4H), 1.49 (pentet, 4H, J = 5.8 Hz), 1.37- 1.41 (m, 2H). HPLC-MScalculated C₂₅H₂₉ClN₆O₃ (M + H⁺): 497.2, found: 497.2. 327

¹H NMR (acetone-d₆) δ 8.06 (br s, 1H), 7.42-7.46 (m, 2H), 7.26-7.31 (m,3H), 6.98-6.99 (m, 1H), 6.95 (d, 1H, J = 7.7 Hz), 6.88 (ddd, 1H, J =8.3, 2.5, 0.8 Hz), 5.51 (d, 1H, J = 4.9 Hz), 4.99-5.09 (m, 2H), 4.89 (q,1H, J = 5.0 Hz), 3.77 (s, 3H), 3.12 (t, 1H, J = 5.7 Hz), 2.44 (br s,3H), 1.84-1.90 (m, 1H), 1.66-1.70 (m, 1H), 1.53 (br s, 4H), 1.37 (br s,2H). HPLC-MS calculated C₂₅H₂₈ClN₅O₃ (M + H⁺): 482.2, found: 482.2. 328

¹H NMR (acetone-d₆) δ 8.41 (d, 1H, J = 1.3 Hz), 8.33 (d, 1H, J = 2.6Hz), 8.11 (dd, 1H, J = 2.6, 1.4 Hz), 7.50-7.54 (m, 2H), 7.47 (t, 1H, J =8.1 Hz), 7.35-7.37 (m, 2H), 7.29-7.33 (m, 2H), 7.17 (ddd, 1H, J = 8.1,2.3, 1.1 Hz), 5.53 (d, 1H, J = 5.8 Hz), 4.58 (q, 1H, J = 5.7 Hz),3.52-3.61 (m, 4H), 2.91 (dd, 1H, J = 13.6, 6.5 Hz), 2.82 (dd, 1H, J =13.6, 6.5 Hz), 2.53 (t, 4H, J = 4.5 Hz). HPLC-MS calculated C₂₄H₂₃ClN₄O₄(M + H⁺): 467.1, found: 467.1. 329

¹H NMR (acetone-d₆) δ 7.96 (s, 1H), 7.39-7.43 (m, 2H), 7.26-7.31 (m,3H), 6.97-6.98 (m, 1H), 6.94 (d, 1H, J = 7.7 Hz), 6.88 (ddd, 1H, J =8.3, 2.5, 0.8 Hz), 5.50 (d, 1H, J = 4.9 Hz), 5.03 (m, 2H), 4.88 (q, 1H,J = 5.0 Hz), 3.77 (s, 3H), 3.57 (s, 2H), 3.50-3.53 (m, 4H), 2.33 (t, 4H,J = 4.3 Hz). HPLC-MS calculated C₂₄H₂₆ClN₅O₄ (M + H⁺): 484.2, found:484.2. 330

¹H NMR (acetone-d₆) δ 8.00 (s, 1H), 7.41-7.45 (m, 2H), 7.26-7.31 (m,3H), 6.98-6.99 (m, 1H), 6.95 (d, 1H, J = 7.7 Hz), 6.88 (ddd, 1H, J =8.3, 2.5, 0.9 Hz), 5.50 (d, 1H, J = 5.2 Hz), 5.01-5.03 (m, 2H), 4.86 (q,1H, J = 5.2 Hz), 3.87 (s, 2H), 3.77 (s, 3H), 2.79 (septet, 1H, J = 6.3Hz), 1.03 (d, 3H, J = 6.2 Hz), 1.02 (d, 3H, J = 6.2 Hz). HPLC-MScalculated C₂₃H₂₆ClN₅O₃ (M + H⁺): 456.2, found: 456.2. 331

¹H NMR (acetone-d₆) δ 7.51- 7.55 (m, 2H), 7.30-7.34 (m, 2H), 7.17-7.23(m, 2H), 6.98 (tt, 1H, J = 9.1, 2.3 Hz), 5.57 (d, 1H, J = 5.8 Hz), 4.61(q, 1H, J = 5.7 Hz), 3.20-3.31 (m, 4H), 2.92-3.05 (m, 4H), 2.69 (t, 4H,J = 4.9 Hz), 1.28 (t, 3H, J = 7.4 Hz). HPLC-MS calculatedC₂₂H₂₄ClF₂N₃O₄S (M + H⁺): 500.1, found: 500.1. 332

¹H NMR (acetone-d₆) δ 7.52- 7.55 (m, 2H), 7.30-7.34 (m, 2H), 7.17-7.23(m, 2H), 6.97 (tt, 1H, J = 9.1, 2.3 Hz), 5.59 (d, 1H, J = 5.8 Hz), 4.60(q, 1H, J = 5.7 Hz), 4.06 (q, 2H, J = 7.1 Hz), 3.35-3.47 (m, 4H), 2.98(dd, 1H, J = 13.5, 6.2 Hz), 2.89 (dd, 1H, J = 13.5, 6.2 Hz), 2.56 (t,4H, J = 5.0 Hz), 1.20 (t, 3H, J = 7.1 Hz). HPLC-MS calculatedC₂₃H₂₄ClF₂N₃O₄ (M + H⁺): 480.1, found: 480.1. 333

¹H NMR (acetone-d₆) δ 7.78 (s, 1H), 7.40-7.44 (m, 2H), 7.28-7.32 (m,2H), 7.10-7.19 (m, 2H), 6.97-7.02 (m, 1H), 5.62 (d, 1H, J = 4.9 Hz),5.01- 5.04 (m, 2H), 4.92-4.96 (m, 1H), 2.51 (d, 2H, J = 6.9 Hz),1.5-1.63 (m, 6H), 1.08-1.20 (m, 3H), 0.85-0.94 (m, 2H). HPLC-MScalculated C₂₅H₂₅ClF₂N₄O₂ (M + H⁺): 487.2, found: 487.2. 335

¹H NMR (acetone-d₆) δ 8.59 (s, 1H), 7.45-7.49 (m, 2H), 7.31-7.34 (m,2H), 7.17-7.22 (m, 2H), 7.02 (tt, 1H, J = 9.1, 2.2 Hz), 5.72 (d, 1H, J =5.5 Hz), 5.20-5.21 (m, 2H), 5.05 (q, 1H, J = 5.2 Hz), 2.55 (s, 3H).HPLC-MS calculated C₂₀H₁₅ClF₂N₄O₃ (M + H⁺): 433.1, found: 433.1. 337

¹H NMR (acetone-d₆) δ 7.94 (s, 1H), 7.43 (d, 2H, J = 8.8 Hz), 7.30 (d,2H, J = 8.8 Hz), 7.12-7.17 (m, 2H), 7.00 (tt, 1H, J = 9.1, 2.1 Hz), 5.63(d, 1H, J = 5.0 Hz), 5.01-5.11 (m, 2H), 4.96 (q, 1H, J = 4.8 Hz), 3.74(s, 2H), 2.56 (s, 4H), 1.53 (br s, 8H). HPLC-MS calculatedC₂₅H₂₆ClF₂N₅O₂ (M + H⁺): 502.2, found: 502.2. 338

¹H NMR (acetone-d₆) δ 7.91 (s, 1H), 7.41-7.44 (m, 2H), 7.29-7.31 (m,2H), 7.12-7.17 (m, 2H), 6.97-7.02 (m, 1H), 5.62 (d, 1H, J = 4.9 Hz),5.01- 5.11 (m, 2H), 4.96 (q, 1H, J = 3.9 Hz), 3.57 (s, 2H), 2.76 (d, 2H,J = 11.3 Hz), 1.91 (t, 2H, J = 11.5 Hz), 1.50 (d, 2H, J = 11.9 Hz),1.18-1.25 (m, 1H), 1.03-1.16 (m, 2H), 0.86 (d, 3H, J = 6.4 Hz). HPLC-MScalculated C₂₅H₂₆ClF₂N₅O₂ (M + H⁺): 502.2, found: 502.2. 339

¹H NMR (acetone-d₆) δ 7.92 (s, 1H), 7.42-7.45 (m, 2H), 729-7.32 (m, 2H),7.11-1.17 (m, 2H), 7.00 (tt, 1H, J = 9.1, 2.3 Hz), 5.64 (d, 1H, J = 5.0Hz), 5.01-5.11 (m, 2H), 4.96 (q, 1H, J = 5.1 Hz), 3.55 (s, 2H), 2.32 (brs, 4H), 1.43-1.49 (m, 4H), 1.31-1.37 (m, 2H). HPLC-MS calculatedC₂₄H₂₄ClF₂N₅O₂ (M + H⁺): 488.2, found: 488.2. 340

¹H NMR (acetone-d₆) δ 7.52 (m, 2H), 7.32 (m, 2H), 7.15- 7.19 (m, 2H),6.94-6.99 (m, 1H), 5.91-5.99 (m, 1H), 5.60- 5.61 (m, 1H), 4.52 (q, 1H, J= 5.3 Hz), 4.03-4.10 (m, 1H), 3.04-3.11 (m, 1H), 2.75-2.91 (m, 2H),2.51-2.62 (m, 2H), 2.10-2.20 (m, 1H), 1.62-1.69 (m, 1H), 1.39 (s, 9H).HPLC- MS calculated C₂₅H₂₈ClF₂N₃O₄ (M + H⁺): 508.2, found: 508.2. 341

¹H NMR (acetone-d₆) δ 7.52 (s, 1H), 7.43-7.46 (m, 2H), 7.29-7.35 (m,2H), 7.11-7.17 (m, 2H), 7.00 (tt, 1H, J = 9.1, 2.3 Hz), 5.62 (d, 1H, J =5.0 Hz), 4.92-4.98 (m, 3H), 4.16 (q, 2H, J = 7.0 Hz), 1.31 (t, 3H, J =7.0 Hz). HPLC-MS calculated C₂₀H₁₇ClF₂N₄O₃ (M + H⁺): 435.1, found:435.1. 342

¹H NMR (acetone-d₆) δ 8.99 (d, 1H, J = 2.3 Hz), 8.37 (dd, 1H, J = 8.3,2.4 Hz), 7.63 (d, 1H, J = 8.3 Hz), 7.45 (d, 2H, J = 8.9 Hz), 7.23-7.29(m, 4H), 7.03 (tt, 1H, J = 9.0, 2.2 Hz), 5.87 (d, 1H, J = 5.0 Hz), 5.56(dd, 1H, J = 14.7, 5.8 Hz), 5.48 (dd, 1H, J = 14.7, 5.8 Hz), 5.21 (q,1H, J = 5.2 Hz). HPLC-MS calculated C₂₃H₁₅Cl₂F₂N₅O₂ (M + H⁺): 503.1,found: 503.1. 343

¹H NMR (acetone-d₆) δ 7.55- 7.58 (m, 2H), 7.32-7.35 (m, 2H), 7.21-7.31(m, 6H), 7.18 (tt, 1H, J = 6.6, 1.4 Hz), 6.99 (tt, 1H, J = 9.1, 2.3 Hz),5.61 (d, 1H, J = 5.9 Hz), 4.60 (q, 1H, J = 5.6 Hz), 3.11-3.15 (m, 1H),2.85-2.99 (m, 3H), 2.48- 2.56 (m, 1H), 2.34-2.41 (m, Hz), 1.78-1.84 (m,2H), 1.69- 1.74 (m, 1H), 1.62 (dq, 1H, J = 12.0, 3.9 Hz). HPLC-MScalculated C₂₇H₂₅ClF₂N₂O₂ (M + H⁺): 483.2, found: 483.2. 345

¹H NMR (acetone-d₆) δ 8.32 (d, 2H, J = 4.7 Hz), 7.5.3-7.57 (m, 2H),7.30-7.35 (m, 2H), 7.21-7.27 (m, 2H), 6.99 (tt, 1H, J = 9.1, 2.3 Hz),6.57 (t, 1H, J = 4.7 Hz), 5.64 (d, 1H, J = 5.8 Hz), 4.64 (q, 1H, J = 5.6Hz), 3.72-3.84 (m, 4H), 3.02 (dd, 1H, J = 13.4, 6.4 Hz), 2.91 (dd, 1H, J= 13.4, 6.4 Hz), 2.64 (t, 4H, J = 5.1 Hz). HPLC-MS calculatedC₂₄H₂₂ClF₂N₅O₂ (M + H⁺): 486.1, found: 486.1. 346

¹H NMR (acetone-d₆) δ 8.12 (ddd, J = 4.9, 2.0, 0.8 Hz, 1H), 7.53-7.57(m, 2H), 7.50 (ddd, J = 8.9, 7.1, 2.0 Hz, 1H) 7.31-7.34 (m, 2H),7.21-7.24 (m, 2H), 6.99 (tt, 1H, J = 9.1, 2.3 Hz), 6.77 (d, 1H, J = 8.6Hz), 6.61 (ddd, J = 6.8, 5.6, 0.7 Hz, 1H), 5.63 (d, 1H, J = 5.8 Hz),4.64 (q, 1H, J = 5.6 Hz), 3.47-3.58 (m, 4H), 3.02 (dd, 1H, J = 13.4, 6.4Hz), 2.92 (dd, 1H, J = 13.4, 6.4 Hz), 2.64 (t, 4H, J = 5.1 Hz). HPLC-MScalculated C₂₅H₂₃ClF₂N₄O₂ (M + H⁺): 485.2, found: 485.0. 347

¹H NMR (acetone-d₆) δ 7.53- 7.57 (m, 2H), 7.30-7.34 (m, 2H), 7.17-7.24(m, 2H), 6.98 (tt, 1H, J = 9.1, 2.3 Hz), 5.60 (d, 1H, J = 5.8 Hz), 4.59(q, 1H, J = 5.6 Hz), 3.04-3.07 (m, 1H), 2.94-3.01 (m, 3H), 2.88 (dd, 1H,J = 13.4, 5.3 Hz), 2.43 (dt, 1H, J = 11.2, 2.3 Hz), 2.35 (dt, 1H, J =11.3, 2.4), 2.30 (s, 3H), 1.99-2.07 (m, 2H), 1.85-1.95 (m, 1H), 1.72-1.82 (m, 1H). HPLC-MS calculated C₂₄H₂₃ClF₂N₄O₃ (M + H⁺): 489.2, found:489.2. 348

¹H NMR (acetone-d₆) δ 8.24 (d, 1H, J = 1.4 Hz), 8.04 (dd, 1H, J = 2.6,1.6 Hz), 7.81 (d, 1H, J = 2.6 Hz), 7.51-7.56 (m, 2H), 7.27-7.33 (m, 3H),7.04- 7.06 (m, 2H), 6.86-6.89 (m, 1H), 5.49 (d, 1H, J = 5.7 Hz), 4.58(q, 1H, J = 5.7 Hz), 3.77 (s, 3H), 3.56-3.67 (m, 4H), 2.98 (dd, 1H, J =13.5, 5.9 Hz), 2.89 (dd, 1H, J = 13.5, 5.7 Hz), 2.7 (t, 4H, J = 5.1 Hz).HPLC-MS calculated C₂₅H₂₆ClN₅O₃ (M + H⁺): 480.2, found: 480.2. 349

¹H NMR (acetone-d₆) δ 7.50- 7.54 (m, 2H), 7.27-7.31 (m, 3H), 7.00-7.02(m, 2H), 6.84- 6.87 (m, 1H), 5.44 (d, 1H, J = 5.7 Hz), 4.53 (q, 1H, J =5.7 Hz), 3.97-4.09 (m, 4H), 3.36- 3.46 (m, 4H), 2.93 (dd, 1H, J = 13.5,5.8 Hz), 2.85 (dd, 1H, J = 13.5, 5.8 Hz), 2.54 (t, 4H, J = 5.0 Hz), 1.32(t, 3H, J = 7.0 Hz), 1.20 (t, 3H, J = 7.1 Hz). HPLC-MS calculatedC₂₅H₃₀ClN₃O₅ (M + H⁺): 488.2, found 488.2. 350

¹H NMR (acetone-d₆) δ 7.51- 7.54 (m, 2H), 7.26-7.32 (m, 3H), 6.99-7.00(m, 2H), 6.84 (ddd, 1H, J = 8.2, 2.5, 0.9 Hz), 5.43 (d, 1H, J = 5.7 Hz),4.61 (septet, 1H, J = 6.0 Hz), 4.53 (q, 1H, J = 5.7 Hz), 4.06 (q, 2H, J= 7.1 Hz), 3.40-3.43 (m, 4H), 2.93 (dd, 1H, J = 13.5, 5.8 Hz), 2.85 (dd,1H, J = 13.5, 5.8 Hz), 2.54 (t, 4H, J = 5.0 Hz), 1.26 (d, 3H, J = 6.0Hz), 1.21 (d, 3H, J = 6.0 Hz), 1.20 (t, 3H, J = 7.1 Hz). HPLC-MScalculated C₂₆H₃₂ClN₃O₅ (M + H⁺): 502.2. found: 502.2. 351

HPLC-MS calculated C₂₁H₁₄ClF₂N₇O₂ (M + H⁺) calc'd 470.1, found: 470.1352

HPLC-MS calculated C₂₁H₁₄ClF₂N₇O₂ (M + H⁺) calc'd 470.1, found: 470.1353

¹H NMR (acetone-d₆) δ 8.74 (ddd, 1H, J = 4.8, 1.7, 0.9 Hz), 8.12 (dt,1H, J = 7.9, 1.0 Hz), 7.97 (dt, 1H, J = 7.7, 1.8 Hz), 7.52 (ddd, 1H, J =7.6, 4.8, 1.2 Hz), 7.46-7.50 (m, 2H), 7.27- 7.32 (m, 4H), 7.02 (tt, 1H,J = 9.1, 2.3 Hz), 5.90 (d, 1H, J = 5.2 Hz), 5.54 (dd, 1H, J = 14.6, 6.0Hz), 5.47 (dd, 1H, J = 14.6, 4.2 Hz), 5.18-5.22 (m, 1H). HPLC-MScalculated C₂₂H₁₅ClF₂N₆O₂ (M + H⁺): 469.1. found: 469.1. 354

¹H NMR (acetone-d₆) δ 8.37- 8.39 (m, 1H), 8.32 (dt, 1H, J = 7.9, 1.0Hz), 8.08 (dt, 1H, J = 7.8, 1.7 Hz), 7.58 (ddd, 1H, J = 7.7, 4.9, 1.2Hz), 7.50-7.54 (m, 2H), 7.32-7.36 (m, 2H), 7.23-7.29 (m, 2H), 7.06 (tt,1H, J = 9.1, 2.3 Hz), 5.85 (d, 1H, J = 6.0 Hz), 5.67-5.69 (m, 2H), 5.17(ddd 1H, J = 6.2, 6.2, 5.2 Hz). HPLC-MS calculated C₂₂H₁₅ClF₂N₆O₂ (M +H⁺): 469.1, found: 469.1. 355

¹H NMR (acetone-d₆) δ 7.56- 7.60 (m, 2H), 7.48-7.51 (m, 2H), 7.29-7.36(m, 4H), 7.24- 7.29 (m, 2H), 7.21 (tt, 1H, J = 6.8, 1.3 Hz), 6.99 (tt,1H, J = 9.1, 2.3 Hz), 5.63 (d, 1H, J = 5.8 Hz), 4.61 (q, 1H, J = 5.7Hz), 3.86 (s, 1H), 2.90-3.02 (m, 2H), 2.78-2.86 (m, 2H), 2.66-2.71 (m,2H), 2.14 (dt, 1H, J = 13.2, 5.0 Hz), 1.90- 1.98 (m, 1H), 1.68 (dq, 1H,J = 13.3, 2.6 Hz), 1.61 (dq, 1H, J = 13.3, 2.4 Hz). HPLC-MS calculatedC₂₇H₂₅ClF₂N₂O₃ (M + H⁺): 499.2, found: 499.2. 356

¹H NMR (acetone-d₆) δ 7.54- 7.59 (m, 2H), 7.48-7.52 (m, 2H), 7.31-7.36(m, 4H), 7.23- 7.29 (m, 2H), 6.99 (tt, 1H, J = 9.1, 2.3 Hz), 5.62 (d,1H, J = 5.7 Hz), 4.61 (ddd, 1H, J = 6.4, 5.6, 5.6 Hz), 4.01 (s, 1H),2.99 (dd, 1H, J = 13.2, 6.6 Hz), 2.92 (dd, 1H, J = 13.2, 6.6 Hz),2.64-2.88 (m, 4H), 2.11 (dt, 1H, J = 12.9, 4.8 Hz), 1.91 (dt, 1H, J =13.2, 5.1 Hz), 1.68 (dq, 1H, J = 13.3, 2.6 Hz), 1.60 (dq, 1H, J = 13.3,2.6 Hz). HPLC-MS calculated C₂₇H₂₄Cl₂F₂N₂O₃ (M + H⁺): 533.1, found:533.1. 357

¹H NMR (acetone-d₆) δ 7.54 (d, 1H, J = 7.0 Hz), 7.42-7.46 (m, 2H),7.30-7.34 (m, 2H), 7.19-7.25 (m, 2H), 7.00 (tt, 1H, J = 9.1, 2.3 Hz),6.23 (s, 1H), 6.11 (dd, 1H, J = 7.0, 1.9 Hz), 5.64 (d, 1H, J = 6.3 Hz),4.82 (ddd, 1H, J = 6.1, 6.1, 4.0 Hz), 4.56 (dd, 1H, J = 14.2, 3.9 Hz),4.47 (dd, 1H, J = 14.1, 4.0 Hz), 2.15 (d, 3H, J = 0.9 Hz). HPLC-MScalculated C₂₂H₁₇ClF₂N₂O₃ (M + H⁺): 431.1. found: 431.1. 358

¹H NMR (acetone-d₆) δ 7.99 (d, 1H, J = 5.2 Hz), 7.54-7.58 (m, 2H),7.32-7.36 (m, 2H), 7.21-7.27 (m, 2H), 7.01 (tt, 1H, J = 9.1, 2.3 Hz),6.83 (d, 1H, J = 5.2 Hz), 6.62 (s, 1H), 5.75 (d, 1H, J = 5.5 Hz), 4.82(ddd, 1H, J = 5.5, 4.1, 4.1 Hz), 4.69-4.77 (m, 2H), 2.29 (s, 3H).HPLC-MS calculated C₂₂H₁₇ClF₂N₂O₃ (M + H⁺): 431.1. found: 431.1. 359

¹H NMR (acetone-d₆) δ 9.21 (t, 1H, J = 1.4 Hz), 8.04 (s, 1H), 7.75 (dd,1H, J = 9.4, 1.7 Hz), 7.64-7.66 (m, 2H), 7.46- 7.50 (m, 2H), 7.26-7.31(m, 4H), 7.05 (tt, 1H, J = 9.1, 2.3 Hz), 5.89 (d, 1H, J = 5.2 Hz), 5.54(dd, 1H, J = 14.7, 5.9 Hz), 5.46 (dd, 1H, J = 14.7, 3.9 Hz), 5.20 (ddd,1H, J = 5.6, 5.6, 3.9 Hz). HPLC-MS calculated C₂₄H₁₆ClF₂N₇O₂ (M + H⁺):508.1. found: 508.1. 360

¹H NMR (acetone-d₆) δ 8.41- 8.42 (m, 1H), 8.00-8.03 (m, 1H), 7.73-7.78(m, 1H), 7.53- 7.56 (m, 2H), 7.29-7.36 (m, 2H), 7.21-7.26 (m, 2H), 7.15-7.19 (m, 1H), 6.95-7.01 (m, 1H), 5.68 (d, 1H, J = 5.9 Hz), 4.70 (q, 1H,J = 5.8 Hz), 3.92- 4.02 (m, 2H), 3.43-3.54 (m, 2H), 3.15 (dd, 1H, J =13.6, 5.7 Hz), 3.02-3.07 (m, 3H). HPLC-MS calculated C₂₅H₂₁ClF₂N₄O₃ (M +H⁺): 499.1. found: 499.1. 361

¹H NMR (acetone-d₆) δ 8.25 (d, 1H, J = 1.5 Hz), 8.04 (dd, 1H, J = 2.5,1.5 Hz), 7.81 (d, 1H, J = 2.6 Hz), 7.53-7.60 (m, 2H), 7.30-7.34 (m, 2H),7.21- 7.27 (m, 2H), 6.99 (tt, 1H, J = 9.1, 2.3 Hz), 5.64 (d, 1H, J = 5.8Hz), 4.65 (q, 1H, J = 5.8 Hz), 3.55-3.67 (m, 4H), 3.04 (dd, 1H, J =13.5, 6.3 Hz), 13.5, 5.4 Hz), 2.93 (dd, 1H, J = 13.5, 5.4 Hz), 2.72 (t,4H, J = 5.1 Hz). HPLC-MS calculated C₂₄H₂₂ClF₂N₅O₂ (M + H⁺): 486.2.found: 486.2. 362

¹H NMR (acetone-d₆) δ 7.54- 7.58 (m, 2H), 7.31-7.35 (m, 2H), 7.22-7.29(m, 2H), 6.99 (tt, 1H, J = 9.1, 2.3 Hz), 6.89 (s, 3H), 5.67 (d, 1H, J =5.9 Hz), 4.68 (q, 1H, J = 5.7 Hz), 3.57-3.69 (m, 2H), 3.32-3.43 (m, 2H),3.13 (dd, 1H, J = 13.6, 5.8 Hz), 3.01-3.07 (m, 3H), 2.27 (s, 6H).HPLC-MS calculated C₂₈H₂₆ClF₂N₃O₃ (M + H⁺): 526.2. found: 526.2. 364

¹H NMR (CDCl₃) δ 9.21 (s, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 7.75 (s, 1H),7.67-7.62 (m, 2H), 7.52-7.44 (m, 4H), 7.34-7.28 (m, 3H), 5.85 (d, J =5.5 Hz, 1H), 5.17-5.07 (m, 2H), 4.26 (dd, J = 6.6, 6.6 Hz, 1H), 2.10(ovlp s, 3H); HPLC- MS calculated C₂₇H₂₀ClF₄N₅O₃ (M + H⁺): 574.1, found:574.1. 365

¹H NMR (CDCl₃) δ 8.00 (s, 1H), 7.73 (s, 1H), 7.64 (m, 1H), 7.51 (d, J =8.4 Hz, 1H), 7.46-7.42 (m, 3H), 7.33-7.29 (m, 2H), 5.96 (d, J = 2.2 Hz,1H), 5.78 (d, J = 5.4 Hz, 1H), 5.29 (s, 2H), 5.12-5.10 (m, 2H), 5.03(ddd, J = 5.8, 5.5, 4.2 Hz, 1H), 4.91 (d, J = 2.6 Hz, 1H), 2.14 (s, 3H);HPLC- MS calculated C₂₄H₁₉ClF₄N₆O₂ (M + H⁺): 535.1, found: 535.1. 366

¹H NMR (CDCl₃) δ 7.90 (s, 1H), 7.74 (s, 1H), 7.66-7.63 (m, 1H), 7.52 (d,J = 8.4 Hz, 1H), 7.47-7.43 (m, 2H), 7.34- 7.31 (m, 2H), 7.28-7.26 (m,1H), 6.04-5.98 (m, 1H), 5.79 (d, J = 5.2 Hz, 1H), 5.33 (s, 2H),5.12-5.10 (m, 2H), 5.03 (ddd, J = 5.8, 5.5, 4.2 Hz, 1H), 4.96 (d, J =2.4 Hz, 1H), 2.32 (s, 3H); HPLC-MS calculated C₂₄H₁₉ClF₄N₆O₂ (M + H⁺):535.1, found: 535.1. 367

¹H NMR (acetone-d₆) δ 7.54- 7.50 (m, 2H), 7.32-7.28 (m, 3H), 7.03-7.01(m, 2H), 6.89- 6.86 (m, 1H), 5.44 (d, J = 5.7 Hz, 1H), 4.53 (q, J = 5.7Hz, 1H), 4.07 (q, J = 6.8 Hz, 2H), 3.77 (s, 3H), 3.42-3.39 (m, 4H), 2.95(dd, J = 13.5, 5.9 Hz, 1H), 2.86 (dd, part. Obs by HOD, 1H), 2.51 (t, J= 4.8 Hz, 4H), 1.20 (t, J = 6.8 Hz, 3H); HPLC-MS calculated C₂₄H₂₈ClN₃O₅(M + H⁺) 474.2, found 474.2. 369

¹H NMR (acetone-d₆) δ 9.07 (d, J = 1.6 Hz, 1H), 8.62 (s, 1H), 8.54 (dd,J = 4.8, 1.6 Hz, 1H), 8.21 (dt, J = 7.9, 2.1 Hz, 1H), 7.45-7.41 (m, 3H),7.32- 7.26 (m, 3H), 7.03-6.99 (m, 2H), 6.89 (ddd, J = 8.3, 2.6, 0.9 Hz,1H), 5.58 (d, J = 5.4 Hz, 1H), 5.16-5.14 (m, 2H), 4.95 (ddd, J = 5.5,5.5, 4.6 Hz, 1H), 3.76 (s, 3H); HPLC-MS calculated C₂₄H₂₀ClN₅O₃ (M + H⁺)462.1, found 462.1. 370

¹H NMR (acetone-d₆) δ 8.56 (s, 1H), 7.98-7.95 (m, 2H), 7.73-7.71 (m,2H), 7.31-7.28 (m, 2H), 7.19-7.13 (m, 3H), 6.90-6.87 (m, 2H), 6.76 (ddd,J = 8.3, 2.6, 0.9 Hz, 1H), 5.45 (d, J = 5.4 Hz, 1H), 5.04-5.02 (m, 2H),4.84 (ddd, J = 5.5, 5.5, 4.6 Hz, 1H), 3.63 (s, 3H); HPLC-MS calculatedC₂₆H₂₀ClN₅O₃ (M + H⁺) 486.1, found 486.1. 371

¹H NMR (acetone-d₆) δ 8.05 (s, 1H), 7.43-7.41 (m, 2H), 7.32-7.28 (m,3H), 6.99-6.95 (m, 2H), 6.88 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 5.52 (d, J= 5.2 Hz, 1H), 5.05-5.04 (m, 2H), 4.88 (ddd, J = 5.2, 5.2, 4.6 Hz, 1H),4.60-4.53 (m, 2H), 4.20-4.16 (m, 1H), 3.77 (s, 3H), 3.75-3.65 (m, 4H),1.95-1.88 (m, 2H); HPLC-MS calculated C₂₄H₂₅ClN₄O₅ (M + H⁺) 485.2, found485.1. 372

¹H NMR (acetone-d₆) δ 8.07- 8.04 (m, 2H), 7.59-7.55 (m, 3H), 7.54-7.45(m, 3H), 7.42- 7.38 (m, 2H), 7.30-7.26 (m, 2H), 7.18-7.13 (m, 1H), 5.85(d, J = 5.0 Hz, 1H), 5.50 (dd, J = 14.7, 5.9 Hz, 1H), 5.43 (dd, J =14.7, 4.0 Hz, 1H), 5.19-5.15 (m, 1H), HPLC- MS calculated C₂₃H₁₇ClFN₅O₂(M + H⁺) 450.1, found 450.1. 373

¹H NMR (acetone-d₆) δ 8.38 (s, 1H0, 7.61 (br s, 1H), 7.47- 7.42 (m, 2H),7.33-7.27 (m, 3H), 7.21 (br s, 1H), 7.03 (t, J = 2.0 Hz, 1H), 6.99 (d, J= 7.7 Hz, 1H), 6.89 (dd, J = 8.3, 2.5 Hz, 1H), 5.59 (d, J = 5.3 Hz, 1H),5.16 (dd, J = 14.7, 5.9 Hz, 1H), 5.11 (dd, J = 14.7, 4.3 Hz, 1H), 4.95(ddd, J = 5.5, 5.5, 4.3 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H); HPLC-MScalculated C₂₃H₂₁ClN₆O₃ (M + H⁺) 465.1, found 465.1. 374

¹H NMR (CDCl₃) δ 8.92 (s, 1H), 7.71 (s, 1H), 7.72-7.69 (m, 1H), 7.52 (d,J = 8.4 Hz, 1H), 7.50-7.46 (m, 2H), 7.33- 7.20 (m, 2H), 5.90 (d, J = 5.6Hz, 1H), 5.34-5.33 (m, 2H), 5.18 (ddd, J = 5.7, 5.7, 4.7 Hz, 1H), 2.40(s, 3H); HPLC-MS calculated C₂₂H₁₅ClF₄N₆O₃ (M + H⁺): 523.1, found:523.1. 375

¹H NMR (acetone-d₆) δ 7.54 (s, 1H), 7.44-7.42 (m, 2H), 7.32-7.28 (m,3H), 6.99-6.95 (m, 2H), 6.88 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 5.48 (d, J= 5.2 Hz, 1H), 4.94-4.92 (m, 2H), 4.85 (ddd, J = 5.5, 5.1, 4.4 Hz, 1H),4.15 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H);HPLC-MS calculated C₂₁H₂₁ClN₄O₄ (M + H⁺) 429.1, found 429.1. 376

¹H NMR (acetone-d₆) δ 8.93 (s, 1H), 7.47-7.44 (m, 2H), 7.33-7.28 (m,3H), 7.05-7.00 (m, 2H), 6.88 (ddd, J = 7.9, 2.5, 0.8 Hz, 1H), 5.62 (d, J= 5.0 Hz, 1H), 5.25-5.24 (m, 2H), 5.03 (ddd, J = 5.7, 5.5, 4.9 Hz, 1H)3.76 (s, 3H), 2.40 (s, 3H); HPLC-MS calculated C₂₂H₁₉ClN₆O₄ (M + H⁺)467.1, found 467.1.1. 378

¹H NMR (acetone-d₆) δ 8.05- 8.03 (m, 2H), 7.54-7.50 (m, 3H), 7.47-7.43(m, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.30-7.24 (m, 2H), 7.09 (t, J = 2.08Hz, 1H), 7.05-7.03 (app d, J = 7.8 Hz, 1H), 6.90 (ddd, J = 8.3, 2.6, 0.9Hz, 1H), 5.72 (d, J = 5.1 Hz, 1H), 5.50 (dd, J = 14.7, 8.7 Hz, 1H), 5.43(dd, J = 14.7, 10.6 Hz, 1H), 5.12- 5.08 (m, 1H), 3.76 (s, 3H), HPLC-MScalculated C₂₄H₂₀ClN₅O₃ (M + H⁺) 462.1, found 462.1. 379

¹H NMR (acetone-d₆) δ 7.48- 7.44 (m, 2H), 7.34-7.29 (m, 3H), 7.07 (appt, J = 2.1 Hz, 1H), 7.02-6.99 (app d, J = 7.7 Hz, 1H), 6.90 (ddd, J =8.3, 2.6, 0.9 Hz, 1H), 5.61 (d, J = 5.4 Hz, 1H), 5.40 (dd, J = 14.6, 6.4Hz, 1H), 5.30 (dd, J = 14.6, 4.0 Hz, 1H), 5.02 (ddd, J = 6.4, 5.4, 4.1Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.94 (gem, d, J = 16.4 Hz, 2H), 3.78(s, 3H), 1.20 (t, J = 7.1 Hz, 3H); HPLC-MS calculated C₂₂H₂₂ClN₅O₅ (M +H⁺) 472.1, found 472.1. 383

¹H NMR (acetone-d₆) δ 9.20 (dd, J = 2.2, 0.9 Hz, 1H), 8.71 (dd, J = 4.8,1.7 Hz, 1H), 8.32 (ddd, J = 8.0, 2.2, 1.8 Hz, 1H), 7.52 (ddd, J = 7.9,4.8, 0.9, Hz, 1H), 7.46-7.42 (m, 2H), 7.32 (t, J = 7.9 Hz, 1H),7.27-7.24 (m, 2H), 7.09 (app t, J = 2.1 Hz, 1H), 7.04 (d, J = 7.7 Hz,1H), 6.92 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 5.72 (d, J = 5.1 Hz, 1H),5.51 (dd, J = 14.7, 6.0 Hz, 1H), 5.45 (dd, J = 14.7, 4.0 Hz, 1H), 5.12(ddd, J = 5.9, 5.2, 4.1 Hz, 1H), 3.77 (s, 3H), HPLC-MS calculatedC₂₃H₁₉ClN₆O₃ (M + H⁺) 463.1, found 463.1. 385

¹H NMR (acetone-d₆) δ 7.87 (s, 1H), 7.46-7.42 (m, 2H), 7.29-7.25 (m,3H), 6.92-6.88 (m, 2H), 6.85 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 5.47 (d, J= 4.8 Hz, 1H), 4.67 (ddd, J = 5.4, 5.4, 4.9 Hz, 1H), 4.28 (d, J = 7.2Hz, 2H), 4.06-3.96 (m, 4H), 3.76 (s, 3H), 3.33 (d, J = 5.4 Hz, 2H),2.67-2.52 (m, 4H), 1.50-1.42 (m, 1H), 1.41 (s, 9H); HPLC-MS calculatedC₃₀H₃₆ClN₅O₅ (M + H⁺-Boc) 482.2, found 482.2. 388

¹H NMR (acetone-d₆) δ 8.03 (s, 1H), 7.46-7.42 (m, 2H), 7.32-7.30 (m,2H), 7.19-7.15 (m, 2H), 7.00 (dddd, J = 9.1, 9.1, 2.3, 2.3 Hz, 1H), 5.64(d, J = 5.3 Hz, 1H), 5.09-5.08 (m, 2H), 4.95 (ddd, J = 5.4, 5.4, 4.3 Hz,1H), 4.58-4.53 (m, 2H), 4.22-4.18 (m, 1H), 3.77- 3.64 (m, 6H); HPLC-MScalculated C₂₃H₂₁ClF₂N₄O₄ (M + H⁺): 491.1, found: 491.1. 390

¹H NMR (acetone-d₆) δ 9.20 (br s, 1H), 8.72 (d, J = 4.1, 1H), 8.34 (ddd,J = 8.0, 1.9, 1.9 Hz, 1H), 7.52 (ddd, J = 7.9, 4.8, Hz, 1H), 7.46-7.42(m, 2H), 7.29-7.24 (m, 2H), 7.02 (dddd, J = 9.1, 9.1, 2.2, 2.2 Hz, 1H),5.87 (d, J = 5.1 Hz, 1H), 5.51 (dd, J = 14.7, 5.7 Hz, 1H), 5.46 (dd, J =14.7, 4.0 Hz, 1H), 5.12 (ddd, J = 5.4, 5.4, 4.0 Hz, 1H), HPLC-MScalculated C₂₂H₁₅ClF₂N₆O₂ (M + H⁺) 469.1, found 469.1. 393

¹H NMR (acetone-d₆) δ 7.48- 7.45 (m, 2H), 7.34-7.31 (m, 2H), 7.20-7.18(m, 2H), 7.02 (dddd, J = 9.1, 9.1, 2.3, 2.3 Hz, 1H), 5.76 (d, J = 4.8Hz, 1H), 5.38 (dd, J = 14.7, 5.4 Hz, 1H), 5.30 (dd, J = 14.7, 4.2 Hz,1H), 5.12 (ddd, J = 5.2, 5.1, 4.1 Hz, 1H), 4.05- 3.98 (m, 2H), 3.06(dddd, J = 11.1, 11.1, 4.0, 4.0 Hz, 1H), 1.85-1.80 (m, 2H), 1.63-1.53(m, 2H), 1.41 (s, 9H), HPLC- MS calculated C₂₇H₂₉ClF₂N₆O₂ (M + H⁺-Boc)475.2, found 475.2. 394

¹H NMR (acetone-d₆) δ 7.52- 7.48 (m, 2H), 7.38-7.32 (m, 2H), 7.26-7.23(m, 2H), 7.02 (dddd, J = 9.1, 9.1, 2.3, 2.3 Hz, 1H), 5.76 (d, J = 5.2Hz, 1H), 5.27-5.17 (m, 3H), 5.03 (ddd, J = 6.0, 5.3, 4.3 Hz, 1H),4.17-4.13 (m, 2H), 3.06 (dddd, J = 11.1, 11.1, 3.3, 3.3 Hz, 1H),1.99-1.95 (m, 2H), 1.84-1.73 (m, 2H), 1.46 (s, 9H), HPLC-MS calculatedC₂₇H₂₉ClF₂N₆O₄ (M + H⁺-Boc) 475.2, found 475.2. 395

¹H NMR (acetone-d₆) δ 7.78- 7.76 (m, 2H), 7.66 (s, 1H), 7.45 (d, J = 8.9Hz, 1H), 7.36- 7.27 (m, 3H), 7.20-7.14 (m, 2H), 7.01-6.87 (m, 1H), 5.60(d, J = 5.5 Hz, 1H), 4.93-4.89 (m, 1H), 4.75-4.74 (m, 2H); HPLC-MScalculated C₂₅H₁₈ClF₂N₃O₂ (M + H⁺) 466.1, found 466.1. (Proton countshort) 396

¹H NMR (acetone-d₆) δ 8.79 (m, 1H), 8.21 (ddd, J = 8.7, 2.4, 1.3 Hz,1H), 7.45 (d, J = 9.0 Hz, 2H) 7.29-7.24 (m, 4H), 7.05-7.00 (m, 1H), 6.90(d, J = 8.7 Hz, 1H), 5.87 (d, J = 4.9 Hz, 1H), 5.49 (dd, J = 14.7, 5.6Hz, 1H), 5.43 (dd, J = 14.7, 4.1 Hz, 1H), 5.12 (ddd, J = 5.3, 5.0, 4.2Hz, 1H), 3.97 (s, 3H), HPLC-MS calculated C₂₃H₁₇ClF₂N₆O₃ (M + H⁺) 499.1,found 499.0. 397

¹H NMR (acetone-d₆) δ 8.32 (d, J = 4.7 Hz, 2H), 7.55-7.53 (m, 2H),7.33-7.29 (m, 3H), 7.06-7.04 (m, 2H), 6.87 (ddd, J = 8.3, 2.5, 0.8 Hz,1H), 6.57 (t, J = 4.7 Hz, 1H), 5.49 (d, J = 5.7 Hz, 1H), 4.57 (q, J =5.7 Hz, 1H), 3.80-3.77 (m, 7H), 2.98 (dd, J = 13.4, 6.1 Hz, 1H), 2.86(dd, J = 13.4, 5.6 Hz, 1H), 2.62 (t, J = 5.1 Hz, 4H); HPLC-MS calculatedC₂₅H₂₆ClN₅O₃ (M + H⁺) 480.1, found 480.1. 398

¹H NMR (acetone-d₆) δ 8.12 (dddd, J = 4.1, 2.0, 1.2, 0.8 Hz, 1H),7.56-7.48 (m, 3H), 7.32-7.28 (m, 3H), 7.06-7.04 (m, 2H), 6.90-6.76 9m,1H), 6.77 (d, J = 8.6 Hz, 1H), 6.61 (ddd, J = 6.8, 5.6, 0.7 Hz, 1H),5.49 (d, J = 5.6 Hz, 1H), 4.57 (q, J = 5.8 Hz, 1H), 3.77 (s, 3H),3.55-3.51 (m, 4H), 2.96 (dd, J = 13.4, 6.1 Hz, 1H), 2.87 (dd, J = 13.4,5.6 Hz, 1H), 2.67 (t, J = 5.0 Hz, 4H); HPLC-MS calculated C₂₆H₂₇ClN₄O₃(M + H⁺) 479.2, found 479.1. 401

¹H NMR (acetone-d₆) δ 8.79 (dd, J = 2.4, 0.8 Hz, 1H), 8.19 (dd, J = 8.7,2.4 Hz, 1H), 7.94 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.73-7.65 (m, 2H),7.46- 7.43 (m, 2H), 7.26-7.24 (m, 2H), 6.90 (dd, J = 8.7, 0.8 Hz, 1H),5.95 (d, J = 4.8 Hz, 1H), 5.52 (dd, J = 14.6, 5.6 Hz, 1H), 5.43 (dd, J =14.6, 4.1 Hz, 1H), 5.12 (ddd, J = 5.6, 4.8, 4.1 Hz, 1H), 3.96 (s, 3H),HPLC-MS calculated C₂₄H₁₈ClF₃N₆O₃ (M + H⁺) 531.1, found 531.1. 402

¹H NMR (acetone-d₆) δ 9.06 (d, J = 2.3 Hz, 1H), 8.19 (dd, J = 8.1, 2.3Hz, 1H), 7.44- 7.41 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 7.9Hz, 1H), 7.25-7.23 (m, 2H), 7.08 (app t, J = 2.1 Hz, 1H), 7.03 (d, J =7.7 Hz, 1H), 6.92 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 5.71 (d, J = 5.1 Hz,1H), 5.48 (dd, J = 14.6, 5.9 Hz, 1H), 5.40 (dd, J = 14.6, 4.0 Hz, 1H),5.12 (ddd, J = 5.9, 5.1, 4.1 Hz, 1H), 3.76 (s, 3H), 2.56 (s, 3H),HPLC-MS calculated C₂₄H₂₁ClN₆O₃ (M + H⁺) 477.1, found 477.1. 403

¹H NMR (acetone-d₆) δ 8.78 (dd, J = 2.4, 0.8 Hz, 1H), 8.19 (dd, J = 8.7,2.4 Hz, 1H), 7.59-7.54 (m, 3H), 7.46-7.43 (m, 2H), 7.35-7.32 (m, 1H),7.27-7.24 (m, 2H), 6.90 (dd, J = 8.7, 0.8 Hz, 1H), 5.89 (d, J = 4.8 Hz,1H), 5.49 (dd, J = 14.7, 5.6 Hz, 1H), 5.43 (dd, J = 14.6, 4.0 Hz, 1H),5.12 (ddd, J = 5.6, 4.8, 4.1 Hz, 1H), 3.96 (s, 3H), HPLC-MS calculatedC₂₄H₁₈ClF₃N₆O₄ (M + H⁺) 547.1, found 547.0. 404

¹H NMR (acetone-d₆) δ 7.55- 7.48 (m, 5H), 7.33-7.28 (m, 3H), 5.62 (d, J= 5.7 Hz, 1H), 4.60 (ddd, J = 6.4, 5.5, 5.5 Hz, 1H), 4.07 (q, J = 7.1Hz, 2H), 3.45-3.34 (m, 4H), 2.98 (dd, J = 13.5, 6.4 Hz, 1H), 2.86 (dd, J= 13.5, 5.3 Hz, 1H), 2.55 (t, J = 5.1 Hz, 4H), 1.20 (t, J = 7.1 Hz, 3H);HPLC-MS calculated C₂₄H₂₅ClF₃N₃O₅ (M + H⁺) 528.1, found 528.1. 405

¹H NMR (acetone-d₆) δ 9.07 (m, 1H), 8.58 (s, 1H), 8.19 (dd, J = 8.1, 2.2Hz, 1H), 7.44-7.41 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.36-7.22, 6.96(d, J = 7.7 Hz, 1H), 6.92 (s, 1H), 6.83 (ddd, J = 8.1, 2.4, 1.3 Hz, 1H),5.65 (d, J = 4.6 Hz, 1H), 5.48 (dd, J = 14.6, 5.8 Hz, 1H), 5.40 (dd, J =14.6, 3.9 Hz, 1H), 5.12 (ddd, J = 5.7, 5.4, 4.3 Hz, 1H), 2.56 (s, 3H),HPLC-MS calculated C₂₃H19Cl₆O₃ (M + H⁺) 463.1, found 462.9. 406

¹H NMR (acetone-d₆) δ 9.08 (d, J = 2.2 Hz, 1H), 8.19 (dd, J = 8.1, 2.3Hz, 1H), 7.47- 7.42 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.26-7.24 (m, 2H), 7.05 (app t, J = 2.0 Hz, 1H), 7.03 (d, J =7.7 Hz, 1H), 6.92 (ddd, J = 8.3, 2.5, 0.8 Hz, 1H), 5.70 (d, J = 5.0 Hz,1H), 5.48 (dd, J = 14.6, 5.8 Hz, 1H), 5.41 (dd, J = 14.6, 4.1 Hz, 1H),5.12 (ddd, J = 5.7, 5.0, 4.2 Hz, 1H), 4.61 (septet, J = 6.0 Hz, 1H),1.25 (d, J = 6.0 Hz, 3H), 1.21 (d, J = 6.0 Hz, 3H), HPLC-MS calculatedC₂₆H₂₅ClN₆O₃ (M + H⁺) 505.2, found 505.2. 407

¹H NMR (acetone-d₆) δ 8.78 (dd, J = 2.4, 0.7 Hz, 1H), 8.20 (dd, J = 8.7,2.4 Hz, 1H), 7.47-7.42 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.26-7.24 (m,2H), 7.08 (app t, J = 2.0 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.92-6.89(m, 2H), 5.70 (d, J = 5.0 Hz, 1H), 5.46 (dd, J = 14.6, 5.8 Hz, 1H), 5.39(dd, J = 14.6, 4.1 Hz, 1H), 5.12 (ddd, J = 5.7, 5.0, 4.1 Hz, 1H), 3.96(s, 3H), 3.77 (s, 3H); HPLC-MS calculated C₂₄H₂₁ClN₆O₄ (M + H⁺) 493.1,found 492.9. 408

¹H NMR (acetone-d₆) δ 8.42 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 9.1, 2.4Hz, 1H), 7.55- 7.52 (m, 2H), 7.33-7.28 (m, 3H), 7.06-7.04 (m, 2H), 6.90-6.87 (m, 2H), 5.49 (d, J = 5.7 Hz, 1H), 4.57 (q, J = 5.7 Hz, 1H), 3.77(s, 3H), 3.72 (ddd, J = 5.4, 5.0, 5.0 Hz, 4H), 2.98 (dd, J = 13.5, 5.8Hz, 1H), 2.87 (dd, J = 13.5, 5.7 Hz, 1H), 2.67 (t, J = 5.0 Hz, 4H);HPLC-MS calculated C₂₇H₂₆ClN₅O₃ (M + H⁺) 504.2, found 504.0. 409

¹H NMR (acetone-d₆) δ 8.78 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 8.7, 2.4Hz, 1H), 7.47- 7.42 (m, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.26-7.24 (m,2H), 7.08 (br s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.92-6.89 (m, 2H), 5.70(d, J = 4.9 Hz, 1H), 5.46 (dd, J = 14.6, 5.9 Hz, 1H), 5.39 (dd, J =14.6, 4.1 Hz, 1H), 5.12 (ddd, J = 5.1, 4.9, 4.6 Hz, 1H), 4.06-4.00 (m,2H), 3.99 (s, 3H), 3.82 (q, J = 5.2 Hz, 2H); HPLC-MS calculatedC₂₅H₂₃ClN₆O₅ (M + H⁺) 523.1, found 522.9. 410

¹H NMR (acetone-d₆) δ 8.62 (d, J = 1.7 Hz, 1H), 8.09 (dd, J = 8.7, 2.3Hz, 1H), 7.56- 7.53 (m, 2H), 7.34-7.29 (m, 3H), 7.08 (dd, J = 2.3, 1.8Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.90 (ddd, J = 8.3, 2.5, 0.8 Hz, 1H),5.64 (d, J = 5.2 Hz, 1H), 4.86-4.79 (m, 3H), 3.77 (s, 3H); HPLC-MScalculated C₂₃H₁₈ClN₃O₄ (M + H⁺) 436.1, found 436.1. 413

¹H NMR (acetone-d₆) δ 7.69- 7.64 (m, 2H), 7.55-7.53 (m, 2H), 7.31-7.26(m, 3H), 7.07 (dd, J = 2.2, 1.9 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H, 6.87(ddd, J = 8.3, 2.6, 0.8 Hz, 1H), 6.55 (dd, J = 6.2, 2.5 Hz, 1H), 5.54(d, J = 5.8 Hz, 1H), 4.62 (q, J = 5.7 Hz, 1H), 4.01 (ddd, J = 6.8, 4.2,3.0 Hz, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 3.48 (d, J = 16.6 Hz, 1H), 3.43(d, J = 16.6 Hz, 1H), 3.10 (dd, J = 13.5, 5.6 Hz, 1H), 3.06-2.97 (m,3H); HPLC-MS calculated C₂₇H₂₇ClN₄O₅ (M + H⁺) 523.2, found 523.0. 414

¹H NMR (acetone-d₆) δ 7.47- 7.44 (m, 2H), 7.31-7.27 (m, 3H), 7.05 (t, J= 2.0 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.85 (ddd, J = 8.3, 2.6, 0.7Hz, 1H), 5.45 (d, J = 6.1 Hz, 1H), 4.64 (ddd, J = 5.9, 5.1, 5.0 Hz, 1H),3.99-3.95 (m, 4H), 3.77 (s, 3H), 3.64-3.55 (m, 4H), 1.42 (s, 9H);HPLC-MS calculated C₂₉H₃₀ClN₃O₆ (M + Na⁺) 538.0 found 538.0. 415

¹H NMR (acetone-d₆) δ 8.10 (dd, J = 9.8, 5.6 Hz, 1H), 7.56-7.52 (m, 2H),7.32-7.27 (m, 3H), 7.05-7.03 (m, 2H), 6.89-6.86 (m, 1H), 6.52 (dd, J =13.2, 2.1 Hz, 1H), 6.44 (ddd, J = 8.2, 6.9, 2.1 Hz, 1H), 5.48 (d, J =5.7 Hz, 1H), 4.57 (q, J = 5.7 Hz, 1H), 3.77 (s, 3H), 3.57 (dddd, J =13.0, 13.0, 10.0, 5.0 Hz, 4H), 2.97 (dd, J = 13.5, 6.0 Hz, 1H), 2.87(dd, J = 13.4, 5.6 Hz, 1H), 2.67 (t, J = 5.1 Hz, 4H); HPLC-MS calculatedC₂₆H₂₆ClFN₄O₃ (M + H⁺) 497.2, found 497.0. 417

HPLC-MS calculated C₂₄H₃₀ClFN₃O₂ (M + H): 446.19, found: 446.20. 418

HPLC-MS calculated C₂₆H₃₁ClFN₃O₄ (M + H): 504.20, found: 504.20. 420

HPLC-MS calculated for C₂₂H₁₈Cl₃F₃N₃O (M + H⁺) 432.1, found 432.0. 421

HPLC-MS calculated for C₂₄H₂₁ClF₃N₂O₂ (M + H⁺) 461.1, found 461.0. 422

HPLC-MS calculated for C₁₈H₁₈ClF₃N₃O₃S (M + H⁺) 448.0, found 448.0. 423

1H NMR (CDCl3, 400 MHz) δ 7.50-7.39 (m, 4H), 7.23 (d, J = 8.8 Hz, 2H),7.13 (d, J = 9.2 Hz, 2H), 5.22 (dd, J = 9.2, 6.4 Hz, 1H), 3.99 (t, J =9.2 Hz, 1H), 3.78 (t, J = 5.0 Hz, 2H), 3.51-3.32 (m, 2H), 3.30 (dd, J =9.0, 6.2 Hz, 1H); HPLC-MS calculated for C₁₈H₁₇ClF₃N₂O₂ (M + H⁺) 385.0,found 385.0. 424

HPLC-MS calculated for C₁₉H₁₉ClF₃N₂O₂ (M + H⁺) 399.1, found 399.0. 425

HPLC-MS calculated for C₂₁H₂₂ClF₃N₃O₂ (M + H⁺) 440.1, found 440.0. 426

HPLC-MS calculated for C₂₃H₂₄ClF₃N₃O₂ (M + H⁺) 466.1, found 466.0. 427

HPLC-MS calculated for C₂₃H₂₅ClF₃N₄O₂ (M + H⁺) 481.1, found 481.0. 428

HPLC-MS calculated for C₂₇H₃₁ClF₃N₄O₄ (M + H⁺) 567.1, found 467.0. 429

HPLC-MS calculated for C₂₆H₂₁ClF₃N₄O₃ (M + H⁺) 425.1, found 425.1. 430

HPLC-MS calculated for C₂₆H₁₉Cl₂F₃N₃O₂ (M + H⁺) 532.0, found 532.0. 431

¹H NMR (CD₃OD, 400 MHz) δ 7.65 (s, 1H), 7.61-7.52 (m, 3H), 7.42 (d, J =8.8 Hz, 2H), 7.25 (d, J = 9.2 Hz, 2H), 6.76 (s, 1H), 5.59 (dd, J = 9.2,6.0 Hz, 1H), 4.79 (m, 2H), 4.07 (t, J = 9.2 Hz, 1H), 3.94 (s, 3H), 3.36(m, 1H); HPLC-MS calculated for C₂₂H₁₈ClF₃N₃O₄ (M + H⁺) 480.0, found480.0. 433

HPLC-MS calculated for C₂₃H₂₆ClF₃N₃O₂ (M + H⁺) 468.1, found 468.0. 434

HPLC-MS calculated for C₂₃H₂₆ClF₃N₃O₂ (M + H⁺) 468.1, found 468.0. 435

HPLC-MS calculated for C₂₃H₂₇ClF₃N₄O₃S (M + H⁺) 531.1, found 531.1. 436

¹H NMR (CD₃OD, 400 MHz) δ 7.60 (s, 1H), 7.56-7.41 (m, 3H), 7.30 (d, J =8.8 Hz, 2H), 7.13 (d, J = 9.2 Hz, 2H), 5.49 (dd, J = 9.2, 6.0 Hz, 1H),4.64-4.45 (m, 2H), 4.03 (t, J = 9.2 Hz, 1H), 3.37 (dd, J = 9.2, 6.0 Hz,1H), 1.31 (s, 9H); HPLC-MS calculated for C₂₃H₂₃ClF₃N₄O₂ (M + H⁺) 479.1,found 479.1. 437

HPLC-MS calculated for C₂₃H₂₇ClF₃N₄O₃S (M + H⁺) 531.1, found 531.1. 439

¹H NMR (CD₃OD, 400 MHz) δ 7.70 (s, 1H), 7.65-7.51 (m, 3H), 7.38 (d, J =8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 5.54 (dd, J = 9.6, 6.4 Hz, 1H),4.09 (t, J = 9.2 Hz, 1H), 3.82-3.75 (m, 2H), 3.46 (dd, J = 8.8, 6.4 Hz,1H), 3.38-3.34 (m, 6H), 1.96-1.93 (m, 4H); HPLC-MS calculated forC₂₂H₂₄ClF₃N₃O₃S (M + H⁺) 502.1, found 502.1. 440

HPLC-MS calculated for C₂₂H₂₄ClF₃N₃O₄S (M + H⁺) 518.1, found 518.1. 441

HPLC-MS calculated for C₁₉H₂₀Cl F₃N₃O₃S (M + H⁺) 462.0, found 462.0. 442

HPLC-MS calculated for C₂₂H₂₆Cl F₃N₃O₅S (M + H⁺) 536.1, found 536.1. 443

HPLC-MS calculated for C₂₆H₂₅Cl F₃N₄O₂ (M + H⁺) 517.1, found 517.1. 444

HPLC-MS calculated for C₂₈H₃₀Cl F₃N₅O (M + H⁺) 544.2, found 544.2. 446

HPLC-MS calculated for C₂₆H₂₅Cl F₃N₄O (M + H⁺) 501.1, found 501.1. 447

HPLC-MS calculated for C₂₆H₂₇Cl F₃N₄O₃ (M + H⁺) 535.1, found 535.1. 448

HPLC-MS calculated for C₂₇H₂₈Cl F₃N₅O₃S (M + H⁺) 594.1, found 594.1. 449

HPLC-MS calculated for C₂₄H₂₉Cl F₃N₄O₃S (M + H⁺) 545.1, found 545.1. 450

HPLC-MS calculated for C₂₇H₃₅Cl F₃N₄O (M + H⁺) 523.2, found 523.2. 452

¹H NMR (CD₃OD, 400 MHz) δ 7.56 (s, 1H), 7.49-7.40 (m, 3H), 7.24 (d, J =9.2 Hz, 2H), 7.10 (d, J = 9.2 Hz, 2H), 5.41 (dd, J = 9.4, 6.2 Hz, 1H),3.95 (t, J = 9.4 Hz, 1H), 3.71-3.50 (m, 2H), 3.26 (dd, J = 8.8, 6.4 Hz,1H), 2.97-2.85 (m, 2H), 1.27 (s, 9H); HPLC-MS calculated for C₂₄H₂₅ClF₃N₄O₂ (M + H⁺) 493.1, found 493.1. 453

HPLC-MS calculated for C₂₅H₂₀Cl F₃N₅O₂ (M + H⁺) 514.1, found 514.1. 454

HPLC-MS calculated for C₂₈H₂₇ClF₃N₃O₅S (M + H⁺) 610.1, found 610.1. 456

¹H NMR (CDCl₃, 400 MHz) δ 7.40-7.60 (m, 4H), 7.27 (d, J = 8.8 Hz, 2H),7.23 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz,2H), 5.26 (dd, J = 6.8 Hz, 9.2 Hz, 1H), 4.11 (t, J = 9.2 Hz, 1H),3.80-3.90 (m, 1H), 3.65-3.76 (m, 1H), 3.39 (dd, J = 6.8 Hz, 8.8 Hz, 1H),3.32 (t, J = 4.4 Hz, 4H), 3.15- 3.25 (m, 2H), 2.50 (b, 4H), 2.33 (s,3H); HPLC-MS calculated for C₂₉H₃₀ClF₃N₄O₄S (M + H⁺) 623.2, found 623.2.461

HPLC-MS calculated for C₂₄H₂₄ClN₃O₅S (M + H⁺) 501.1, found 501.1. 465

¹H NMR (CDCl₃, 400 MHz) δ 7.31 (d, J = 8.8 Hz, 2H), 7.20- 7.26 (m, 3H),6.81-6.90 (m, 7H), 5.15 (dd, , J = 6.4 Hz, 9.2 Hz, 1H), 3.92-4.04 (m,5H), 3.81 (t, J = 6.4 Hz, 2H), 3.30-3.36 (m, 3H), 2.99 (s, 3H), 2.15 (t,J = 5.6 Hz, 1H); HPLC-MS calculated for C₂₆H₂₇ClN₂O₆S (M + H⁺) 531.1,found 531.1. 466

HPLC-MS calculated for C₃₃H₃₆ClF₃N₄O₆S (M + H⁺) 709.2, found 609.2. 467

¹H NMR (CDCl₃, 400 MHz) δ 7.40-7.60 (m, 4H), 7.27 (d, J = 8.8 Hz, 2H),7.23 (d, J = 9.2 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz,2H), 5.26 (dd, J = 6.4 Hz, 9.2 Hz, 1H), 4.11 (t, J = 9.2 Hz, 1H),3.80-3.90 (m, 1H), 3.65-3.76 (m, 1H), 3.39 (dd, J = 6.8 Hz, 8.8 Hz, 1H),3.20- 3.30 (m, 4H), 3.15-3.25 (m, 2H), 2.90-2.98 (m, 4H); HPLC-MScalculated for C₂₈H₂₈ClF₃N₄O₄S (M + H⁺) 609.2, found 609.2. 469

¹H NMR (CDCl₃, 400 MHz) δ 8.96 (d, J = 3.6 Hz, 1H), 7.51 (dd, , J = 4.4Hz, 8.8 Hz, 1H), 7.42 (t, J = 8.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H),7.13-7.23 (m, 6H), 5.36 (dd, , J = 6.0 Hz, 8.8 Hz, 1H), 4.80 (t, J = 8.8Hz, 1H), 4.28 (dd, , J = 5.6 Hz, 8.4 Hz, 1H); HPLC-MS calculated forC₁₉H₁₄ClN₃O₃ (M + H⁺) 368.1, found 368.1. 470

HPLC-MS calculated for C₂₅H₂₆ClN₅O₅S (M + H⁺) 544.1, found 544.1. 471

HPLC-MS calculated for C₂₆H₂₉ClN₆O₄S (M + H⁺) 557.2, found 557.2. 472

HPLC-MS calculated for C₂₅H₂₆ClN₅O₄S (M + H⁺) 528.1, found 528.1. 473

HPLC-MS calculated for C₂₁H₂₀ClN₅O₄S (M + H⁺) 474.1, found 474.1. 474

HPLC-MS calculated for C₂₀H₂₃ClN₂O₅S (M + H⁺) 439.1, found 439.1. 475

HPLC-MS calculated for C₂₃H₂₈ClN₃O₆S (M + H⁺) 510.1, found 510.1. 476

HPLC-MS calculated for C₂₄H₃₁ClN₄O₅S (M + H⁺) 523.2, found 523.2. 477

HPLC-MS calculated for C₂₃H₂₈ClN₃O₅S (M + H⁺) 494.1, found 494.1. 478

HPLC-MS calculated for C₁₉H₂₂ClN₃O₅S (M + H⁺) 440.1, found 440.1. 479

HPLC-MS calculated for C₂₈H₂₅ClN₄O₅S (M + H⁺) 565.1, found 565.1. 480

HPLC-MS calculated for C₂₅H₁₉ClN₄O₃ (M + H⁺) 459.1, found 459.1. 481

HPLC-MS calculated for C₂₇H₂₄ClN₅O₅S (M + H⁺) 566.1, found 566.1. 482

HPLC-MS calculated for C₂₀H₁₇ClN₄O₃ (M + H⁺) 397.1, found 397.1. 483

HPLC-MS calculated for C₂₃H₂₃ClN₄O₅S (M + H⁺) 503.1, found 503.1. 484

HPLC-MS calculated for C₂₇H₂₅ClF₃N₃O₄S (M + H⁺) 580.1, found 580.1. 485

HPLC-MS calculated for C₂₄H₂₄ClN₅O₄S (M + H⁺) 514.1, found 514.1. 486

HPLC-MS calculated for C₂₉H₂₂ClF₃N₂O₄S (M + H⁺) 587.1, found 587.1. 487

HPLC-MS calculated for C₂₆H₂₁ClN₄O₄S (M + H⁺) 521.1, found 521.1. 488

HPLC-MS calculated for C₂₈H₂₁ClF₃N₃O₄S (M + H⁺) 588.1, found 588.1. 489

HPLC-MS calculated for C₂₅H₂₀ClN₅O₄S (M + H⁺) 522.1, found 522.1. 491

HPLC-MS calculated for C₁₉H₁₈ClF₃N₂O₃S (M + H⁺) 447.1, found 447.1. 492

¹H NMR (CDCl₃, 400 MHz) δ 7.55 (m, 2H), 7.47 (m, 2H), 7.25 (m, 4H), 6.86(m, 4H), 6.33 (br, 1H), 5.65 (br, 1H), 5.24 (dd, J = 9.2, 6.4 Hz, 1H),4.03 (t, J = 9.2 Hz, 1H), 3.70 (dt, J = 14.4, 6.0 Hz, 1H), 3.57 (dt, J =14.4, 6.0 Hz, 1H), 3.31 (dd, J = 9.2, 6.4 Hz, 1H), 2.60 (t, J = 6.0 Hz,2H); HPLC-MS calculated for C₂₅H₂₁ClF₃N₃O₃ (M + H⁺) 504.1, found 504.1.494

HPLC-MS calculated for C₂₃H₁₇ClN₆O₂ (M + H⁺) 445.1, found 445.1. 496

HPLC-MS calculated for C₂₃H₂₂ClN₃O₄S (M + H⁺) 472.1, found 472.1. 497

HPLC-MS calculated for C₂₉H₂₉ClF₃N₃O₂ (M + H⁺) 544.2, found 544.2. 498

¹H NMR (CDCl₃, 400 MHz) δ 7.56-7.44 (m, 4H), 7.29 (d, J = 9.2 Hz, 2H),7.23 (d, J = 9.2 Hz, 2H), 6.85 (m, 4H), 5.20 (dd, J = 9.2, 6.0 Hz, 1H),4.64 (t, J = 4.8 Hz, 1H), 4.07 (m, 2H), 3.92 (t, J = 9.2 Hz, 1H), 3.74(m, 2H), 3.45 (m, 2H), 3.27 (dd, J = 9.2, 6.0 Hz, 1H), 2.05 (m, 1H),1.86 (td, J = 6.8, 4.8 Hz, 2H), 1.33 (m, 1H); HPLC-MS calculated forC₂₈H₂₆ClF₃N₂O₄ (M + H⁺) 547.2, found 547.2. 499

HPLC-MS calculated for C₂₈H₂₅ClF₃N₃O₃ (M + H⁺) 544.2, found 544.2. 500

¹H NMR (CDCl₃, 400 MHz) δ 7.55-7.45 (m, 4H), 7.23 (m, 4H), 6.86 (m, 4H),5.23 (dd, J = 9.2, 7.2 Hz, 1H), 4.34 (t, J = 8.0 Hz, 2H), 4.09 (t, J =9.2 Hz, 1H), 3.83-3.58 (m, 4H), 3.36 (m, 3H); HPLC-MS calculated forC₂₇H₂₃ClF₃N₃O₄ (M + H⁺) 546.1, found 546.1. 501

HPLC-MS calculated for C₂₇H₂₂ClF₃N₄O₂ (M + H⁺) 527.1, found 527.1. 502

HPLC-MS calculated for C₂₇H₂₂ClF₃N₄O₂ (M + H⁺) 527.1, found 527.1. 504

HPLC-MS calculated for C₁₇H₁₅ClF₃N₃O₂S (M + H⁺) 418.1, found 418.1 505

HPLC-MS calculated for C₂₂H₂₂ClN₅O₄S (M + H⁺) 488.1, found 488.1. 506

HPLC-MS calculated for C₁₉H₁₅ClN₄O₂ (M + H⁺) 367.1, found 367.1. 508

¹H NMR (CDCl₃, 400 MHz) δ 8.40 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.08(d, J = 2.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 9.2 Hz, 2H),7.18 (m, 3H), 7.09 (m, 2H), 5.23 (dd, J = 8.8, 6.0 Hz, 1H), 4.05 (t, J =8.8 Hz, 1H), 3.81 (m, 2H), 3.43 (dd, J = 8.8, 6.0 Hz, 1H), 3.33 (m, 2H),2.97 (s, 3H); HPLC-MS calculated for C₂₂H₂₁ClN₄O₄S (M + H⁺) 473.1, found473.1. 509

HPLC-MS calculated for C₂₁H₂₀ClN₅O₄S (M + H⁺) 474.1, found 474.1. 510

HPLC-MS calculated for C₂₅H₂₆ClN₅O₄S (M + H⁺) 528.1, found 528.1. 511

HPLC-MS calculated for C₂₅H₂₆ClN₅O₅S (M + H⁺) 544.1, found 544.1. 512

HPLC-MS calculated for C₂₆H₂₉ClN₆O₄S (M + H⁺) 557.2, found 557.2. 513

HPLC-MS calculated for C₂₅H₂₇ClN₆O₄S (M + H⁺) 543.2, found 543.2. 514

HPLC-MS calculated for C₂₀H₁₈ClN₅O₃S (M + H⁺) 444.1, found 444.1 515

HPLC-MS calculated for C₁₈H₂₀ClN₃O₄S (M + H⁺) 410.1, found 410.1. 516

HPLC-MS calculated for C₁₉H₁₇ClN₆O₃S (M + H⁺) 445.1, found 445.1. 517

HPLC-MS calculated for C₂₀H₁₈ClN₅O₃S (M + H⁺) 444.1, found 444.1. 518

HPLC-MS calculated for C₂₅H₂₅ClN₄O₄ (M + H⁺) 481.2, found 481.2. 519

HPLC-MS calculated for C₂₅H₂₅ClN₂O₅S (M + H⁺) 501.1, found 501.1. 520

¹H NMR (CDCl₃, 400 MHz) δ 8.41 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.03(d, J = 2.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.8 Hz, 2H),7.18 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.42 (br, 1H),5.67 (br, 1H), 5.17 (dd, J = 8.8, 5.2 Hz, 1H), 4.00 (t, J = 8.8 Hz, 1H),3.61 (t, J = 6.0 Hz, 2H), 3.35 (dd, J = 8.8, 5.2 Hz, 1H), 2.51 (m, 2H);HPLC-MS calculated for C₂₂H₂₀ClN₅O₃ (M + H⁺) 438.1, found 438.1. 523

HPLC-MS calculated for C₂₃H₂₀ClN₅O₄S (M + H⁺) 498.1, found 498.1. 524

HPLC-MS calculated for C₂₄H₂₅ClN₄O₄S (M + H⁺) 501.1, found 501.1. 525

HPLC-MS calculated for C₂₂H₂₂ClN₅O₄S (M + H⁺) 488.1, found 488.1.

CBI Biological Assays

Homogenized membranes are prepared from CHO cell clones stablyexpressing a human cannabinoid receptor 1 (CB1) or human cannabinoidreceptor 2 (CB2). Cells are grown and scrapped from 15 cm tissue cultureplates, and then subsequently centrifuged down. Cells are washed oncewith cold PBS, and resuspended in ≦20 ml of Buffer A (20 mM HEPES, pH7.4, 10 mM EDTA, EDTA-free complete protease inhibitor cocktail [1tablet/25 ml]). The cell suspension is homogenized on ice, using aPolytron homogenizer at 25000 rpm at three intervals of 15 seconds each.The homogenate is first centrifuged at 2000 rpm on a tabletop low speedcentrifuge for 10 minutes. The supernatant, after passing through a cellstrainer, is then centrifuged at 50,000×g for 25 minutes at 4° C. Thepellet is resuspended into buffer B (15% glycerol, 20 mM HEPES, pH 7.4,0.1 mM EDTA, EDTA-free complete protease inhibitor cocktail [1 tablet/10ml]). Protein concentration of the prep is determined using the BCAProtein Assay kit using BSA as standard. The membranes are aliquoted andkept frozen at −80° C.

[³H]-CP55940 ligand binding assay: Solutions of test compounds rangingfrom 100 μM to 0.01 nM are prepared in DMSO. The desired amount ofmembrane prep is diluted with ice-cold assay buffer (50 mM Tris-HCl, 2.5mM EDTA, 5 mM MgCl₂, 0.05% BSA, pH 7.4) and vortexed well. 2 μl or lessof compound is distributed into each well of a round-bottom 96-wellpolystyrene assay plate, followed by addition of 100 μl of dilutedmembranes (3-10 μg/well) and the mixture is kept on ice until theaddition of hot CP55940 (final concentration of 0.5 nM). [³H]-CP55940 isdiluted 1:6300 (v/v) with cold assay buffer and 100 μl is added intoeach well. The reaction is carried out at room temperature for 120minutes before the membranes are harvested onto a PerkinElmer UnifilterGF/B-96 filter plate using a Packard Filtermate Harvester. After ninewashes with wash buffer (50 mM Tris-HCl, 2.5 mM EDTA, 5 mM MgCl₂, 0.05%BSA, pH 7.), the filter is dried in a 37° C. oven for 30 minutes.MicroScint-20 is added and the plate sealed for scintillation countingon TopCount. EC₅₀ values are obtained by fitting the data with thesigmoidal dose response curve-fitting tool of GraphPad Prism. Eight ortwelve different concentrations are used to generate a concentrationresponse curve (using three data points per concentration).

GTPγS binding assay: Solutions of test compounds ranging from 100 μM to0.01 nM are prepared in DMSO. The desired amount of membrane prep isdiluted with ice-cold assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10mM MgCl₂, 0.1% Fatty acid-free BSA, 5 μM GDP) and vortexed well. 2 μl orless of compound is distributed into each well of a round-bottom 96-wellpolystyrene assay plate, followed by addition of 100 μl of dilutedmembranes (3-10 μg/well) and the mixture is kept on ice until theaddition of hot GTPγS. [³⁵]-GTPγS (Perkin Elmer NEG030H; 1 μCi/μl, 1250Ci/mmol) is diluted 1:1000 (v/v) with cold assay buffer and 100 μl isadded into each well. The reaction is carried out at room temperaturefor 90 minutes before the membranes are harvested onto PerkinElmerUnifilter GF/B-96 filter plate using a Packard Filtermate Harvester.After several washes with wash buffer (20 mM HEPES, pH 7.4, 100 mM NaCl,10 mM MgCl₂), and a rinse with 95% ethanol, the filter is dried in a 37°C. oven for 30 minutes. MicroScint-20 is added and the plate sealed forscintillation counting on TopCount. EC₅₀ values are obtained by fittingthe GTP [γ-³⁵S] binding data with the sigmoidal dose responsecurve-fitting tool of GraphPad Prism. Six or twelve differentconcentrations are used to generate a concentration response curve(using three data points per concentration).

For each assay, a Cheng-Prusoff correction (Cheng and Prusoff, 1973,Biochem. Pharmacol., 22: 3099-3103) is used to convert the EC₅₀ toinhibition constant K_(i). Thus,

$K_{i} = \frac{{EC}_{50}}{1 + {\left\lfloor L \right\rfloor/K_{d}}}$

where [L] is the concentration of the radio-ligand used in the assay,and K_(d) is the equilibrium binding dissociation constant for theradio-ligand.

Food Intake and Body Weight Gain

To evaluate the efficacy of compounds of the invention on inhibition offood intake and body weight gain, genetically obese (Lep^(ob)/Lep^(ob))mice and diet-induced obese (DIO) mice are used in acute and sub-chronicmodels, respectively.

Male ob/ob mice (age 7-8 weeks old, Jackson Labs, Bar Harbor, Me.) arehoused in groups of four and fed commercial standard pellet diet (LabDiet 5001, PMI Nutrition International, LLC). Diet-induced obese miceare generated using 6-7 weeks old C57BL6 mice (Jackson Labs, Bar Harbor,Me.) placed on high fat diet (D12331, Research Diets) for 12-17 weeks.All mice are maintained on a 12-hour light/dark cycle (lights on at06:00) in a humidity- and temperature-controlled environment with freeaccess to food and water.

The week prior to the start of each study, mice are singly housed and ahabituation to treatment is performed to establish baseline foodconsumption and body weight Animals are randomized into treatment groupsbased on their initial body weight and food consumption.

To determine the acute effects of a single administration of a compoundof the invention (test compound) on food consumption, ob/ob mice aretreated with either vehicle, a known antagonist as a positive control,or with test compound(s). Similarly, to determine more chronic effectsof test compound on food consumption and body weight gain, DIO mice aretreated with either vehicle, a known antagonist as a positive control,or with test compound(s) for up to 7-35 days. Test compounds are dosedat ranges between 0.1 up to 100 mg/kg Animals are treated one hour priorto the start of the dark cycle. Food intake and body weight are recordedmanually using an electronic balance prior to treatment, 16 hourspost-treatment, followed by daily measurements for up to 7-35 days afterthe start of study. Compound efficacy is determined by comparing foodintake and body weight data between vehicle treated, standard positivecontrol treated, and test compound treated mice.

Compounds of Formula I, in free form or in pharmaceutically acceptablesalt form, exhibit valuable pharmacological properties, for example, asindicated by the in vitro tests described in this application. Compoundof the invention show a K_(i) of between 1×10⁻⁵ and 1×10⁻¹⁰M, preferablyless than 500 nM, more preferably less than 100 nM. Additionally,compounds of the invention show a 10 fold, preferably 20, 50 and 100fold, selectivity for CB1 over CB2.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of Formula I:

in which: Y₁ is selected from N and CR₁₁; Y₂ is selected from N and CR₈; Z₁ is selected from S, O, NH, CH—NO₂, NS(O)₂NH₂, NC(O)NH₂, NS(O)₂CH₃, N(OH) and N(CN); or C=Z₁ of Formula I is replaced with CH₂ or S(O)₂; Z₂ is selected from O, —CH₂CHR_(1a)—, —OCHR_(1a)—, —CR_(1a)R_(1b) and —NR_(1a); R_(1a) is selected from hydrogen, cyano, C₁₋₆alkyl, cyano-substituted-C₁₋₆alkyl, C₂₋₆alkenyl, —X₁R₁₂, —X₁NR₁₃S(O)₂R₁₃, —X₁OS(O)₂R₁₃, —X₁NR₁₃X₁OR₁₃, —X₁OR₁₃, —X₁C(O)OR₁₃, —X₁S(O)₂R₁₂, —X₁S(O)₂NR₁₃C(O)R₁₃, —X₁S(O)₂R₁₃, —X₁C(O)R₁₂, —X₁NR₁₃R₁₃, —X₁S(O)₂NR₁₃R₁₃, —X₁OC(O)NR₁₃R₁₃, —X₁C(O)NR₁₂R₁₃, —X₁NR₁₃X₁C(O)NR₁₂, —X₁NR₁₃X₁C(O)NR₁₃R₁₃, —X₁C(O)NR₁₃X₁C(O)OR₁₃, —X₁C(O)NR₁₃X₁NR₁₃R₁₃, —X₁C(O)NR₁₃X₁OR₁₃ and —X₁C(O)NR₁₃X₂OR₁₃; wherein R₁₂ is selected from C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl and C₃₋₁₀heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁₂ is optionally substituted by 1 to 3 radicals independently selected from hydroxy, bis-hydroxy-C₁₋₆alkyl-amino, C₁₋₆alkyl-amino, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy-carbonyl, C₁₋₆alkyl-sulphoxy, C₁₋₆alkyl-carboxy, C₁₋₆alkyl-sulfonyl, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, C₃₋₁₂cycloalkyl, C₃₋₁₀heterocycloalkyl, C₅₋₁₀heteroaryl and C₆₋₁₀aryl optionally substituted with 1 to 3 halo radicals; wherein said cycloalkyl, heterocycloalkyl, heteroaryl and aryl substituents of R₁₂ can be further optionally substituted with 1 to 3 C₁₋₆alkyl radicals; wherein each R₁₃ is independently selected from hydrogen, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, C₆₋₁₀aryl, C₃₋₁₀heterocycloalkyl; wherein said aryl or heterocycloalkyl of R₁₃ is optionally substituted with a group selected from C₁₋₆alkyl and C₁₋₆alkoxy; wherein each X₁ is independently selected from a bond and C₁₋₄alkylene; R_(1b) is selected from hydrogen, C₁₋₆alkyl and C₂₋₆alkenyl; R_(2a) is selected from hydrogen, C₁₋₆alkyl, halo-substituted-C₁₋₆alkyl, C₆₋₁₀aryl, —X₂NR₁₄X₂NR₁₄R₁₄, —X₂NR₁₄C(O)X₂NR₁₄C(O)OR₁₄, —X₂NR₁₄X₂R₁₅, —X₂OC(O)NR₁₄R₁₄, —X₂OC(O)NR₁₄R₁₅, —X₂NR₁₄R₁₄, —X₂NR₁₄S(O)₂R₁₄, —X₂NR₁₄S(O)₂R₁₅, —X₂S(O)₀₋₂R₁₅, —X₂NR₁₄C(O)R₁₄, —X₂NR₁₄C(O)R₁₅, —X₂NR₁₄C(O)X₂NR₁₄R₁₄, —X₂OSi(R₁₄)₃, —X₂OC(O)NR₁₄R₁₅, —X₂C(O)OR₁₄, —X₂OR₁₄, —X₂OX₂R₁₅, —X₂R₁₅ and —X₂C(O)R₁₅; wherein each R₁₄ is independently selected from hydrogen and C₁₋₆alkyl; R₁₅ is selected from cyano, C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₁₂cycloalkyl and C₃₋₁₀heterocycloalkyl; wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁₅ is optionally substituted by 1 to 3 radicals independently selected from hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkyl-sulphoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —X₃NR₁₆R₁₆, —X₃ONR₁₆R₁₆, —X₃OR₁₆, —X₃S(O)₂R₁₆, —X₃NR₁₆C(O)OR₁₆, —X₃NR₁₆S(O)₀₋₂R₁₆, —X₃R₁₆, —X₃C(O)OR₁₆, —X₃C(O)NR₁₆R₁₆, —X₃OC(O)NR₁₆R₁₆, —X₃S(O)₀₋₂NR₁₆R₁₆, —X₃C(O)R₁₆, C₆₋₁₀aryl and C₅₋₁₀heteroaryl; wherein said aryl and heteroaryl substituents of R₁₅ are optionally substituted with 1 to 3 halo radicals; each X₂ and X₃ are independently selected from a bond and C₁₋₄alkylene; and each R₁₆ is independently selected from hydrogen, C₁₋₆alkyl, C₆₋₁₀aryl, C₅₋₁₀heteroaryl, C₃₋₈cycloalkyl and C₃₋₁₂heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R₁₆ is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, C₁₋₆alkyl, C₁₋₆alkyl-carbonyl-amino and C₁₋₆alkoxy; R_(2b) is selected from hydrogen and C₁₋₆alkyl; or R_(2a) and R_(2b) together with the carbon atom to which R_(2a) and R_(2b) are attached form carbonyl; R₃, R₅, R₆ and R₇ are each independently selected from hydrogen, halo and amino; R₄ is selected from hydrogen, halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, cyano-substituted-C₁₋₆alkyl, cyano-substituted-C₁₋₆alkoxy, —OX₅R_(4a) and —OX₅R_(4a); wherein X₅ is selected from a bond and C₁₋₄alkylene; R_(4a) is selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₆₋₁₀aryl and C₅₋₁₀heteroaryl; wherein any cycloalkyl, aryl or heteroaryl of R_(4a) is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, amino, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, hydroxy-substituted-C₁₋₆alkyl, hydroxy-substituted-C₁₋₆alkoxy, cyano-substituted-C₁₋₆alkyl and cyano-substituted-C₁₋₆alkoxy; R₈, R₉, R₁₁ and R_(12a) are each independently selected from hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; R₁₀ is selected from halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted-C₁₋₆alkyl, halo-substituted-C₁₋₆alkoxy, —X₄OR₁₇, —X₄S(O)₀₋₂R₁₇ and —X₄R₁₇; wherein X₄ is selected from a bond and C₁₋₄alkylene; and R₁₇ is selected from C₆₋₁₀aryl and C₅₋₁₀hetyeroaryl; wherein R₁₇ is optionally substituted with 1 to 3 halo radicals; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 in which R_(1a) is selected from cyano, methyl-carbonyl-amino-sulfonyl-ethyl, pyrrolidin-2-onyl-ethyl, imidazolyl-ethyl, oxazolidin-2-only-ethyl, 1-pyrazolyl-ethyl, cyano-methyl, 4′-(4-chlorophenoxy)phenyl, 1,3-dioxanyl-ethyl, allyl, phenyl, pyrazinyl, piperazinyl-sulfonyl-ethyl, azetidinyl-sulfonyl-ethyl, morpholino-sulfonyl-ethyl, pyrrolidinyl-sulfonyl-ethyl, pyrrolidinyl-propyl, pyrrolidinyl-ethyl, piperazinyl-propyl, piperidinyl-sulfonyl-ethyl, pyridazinyl, (5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl, isoxazolyl, piperidinyl-carbonyl-methyl, 3-(N,N-bis(4-methoxyphenyl)sulfamoyl)propyl, methyl-phenyl-sulfonyl, cyanomethyl, 2-oxo-2-(piperidin-1-ylamino)ethyl, propyl-amino-carbonyl-methyl, 2-(carboxymethylamino)-2-oxoethyl), bis-hydroxyethyl-amino-sulfonyl-ethyl, carboxy-methyl-amino-carbonyl-methyl, amino-carbonyl-ethyl, amino-sulfonyl-ethyl, amino-sulfonyl-propyl, methyl-amino-ethyl, piperidinyl-ethyl, piperazinyl-ethyl, methyl-sulfonyl-ethyl, carboxy-methyl, tetrazole-methyl, benzyl, 1,2,4-oxadiazole, 1,2,4-oxadiazole-methyl, 1,2,4-oxadiazole-ethyl, isoxazole-methyl, 2-(2-hydroxyethylamino)-2-oxoethyl, dimethylamino-ethyl-amino-carbonyl-methyl, hydroxyl-ethyl, methoxy-ethyl, hydroxyl-ethyl-amino-ethyl, morpholino-ethyl, methyl-piperazinyl-ethyl, 2-(c arbamoyloxy)ethyl, methyl-sulfonyl-oxy-ethyl, morpholino-carbonyl-methyl, methyl-sulfonyl-piperazinyl-ethyl, 2-morpholinoethyl, amino-ethyl, 2-(3,3-dimethylureido)ethyl, morpholino-carbonyl-amino-ethyl, methyl-sulfonyl-amino-ethyl, pyridinyl-methyl, hydroxyl-propyl, 2-(2,6-dimethylmorpholino)ethyl, 2-(2-methylmorpholino)ethyl, methyl-sulfonyl-propyl and morpholino-propyl; wherein said ring systems of R_(1a) are optionally substituted with 1 to 3 radicals independently selected from halo, trifluoromethyl, methyl, bis-hydroxy-ethyl-amino, t-butyl, t-butoxy-carbonyl, hydroxy, methyl-sulfonyl, amino-sulfonyl, diethyl-amino, morpholino, cyclohexyl, pyridinyl, piperidinyl, pyrrolidinyl, piperazinyl optionally substituted with ethyl or methyl-sulfonyl, methoxy-carbonyl and methoxy; and R_(1b) is selected from hydrogen and allyl.
 3. The compound of claim 2 in which R_(2a) is selected from (4-(azepan-1-yl-methyl)-1H-1,2,3-triazol-1-yl)methyl, diethyl-amino-pyrrolidinyl-methyl, N,N-methyl-(t-butoxy-carbonyl)-amino-pyrrolidinyl-methyl, (4-(5-cyanopyridin-2-yl)piperazin-1-yl)methyl, 5-cyanopyridinyl-oxy-methyl, (4-(6-methoxypyridin-3-yl)-3-oxopiperazin-1-yl)methyl, (4-(6-methoxypyridin-2-yl)-3-oxopiperazin-1-yl)methyl, (4-(6-methoxypyridin-2-yl)piperazin-1-yl)methyl, 4-t-butoxy-carbonyl-2-oxopiperazin-1-yl)methyl, (4-(4-fluoropyridin-2-yl)piperazin-1-yl)methyl, 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-tetrazol-2-yl-methyl, 5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-tetrazol-1-yl-methyl, t-butoxy-carbonyl-piperidinyl-methyl, 4-(4-cyanophenyl)-1H-1,2,3-triazol-1-yl, 4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl, 4-((tetrahydrofuran-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl, 5-phenyl-2H-tetrazol-2-yl, 4-oxadiazolyl-piperidinyl-methyl, 4-(benzyloxycarbonyl)-2-oxopiperazin-1-yl, 4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl, 4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-1-yl, 4-ethoxy-1H-1,2,3-triazol-1-yl, 4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazol-1-yl, 5-(2-ethoxy-2-oxoethyl)-2H-tetrazol-2-yl, 5-(hydroxy-ethyl)-2H-tetrazol-2-yl, (4-(piperidin-1-ylcarbamoyl)-1H-1,2,3-triazol-1-yl)methyl, 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,3-triazol-4-yl, 5-(6-methoxy-pyridin-3-yl)-2H-tetrazol-2-yl-methyl, 5-(pyridin-3-yl)-2H-tetrazol-2-yl-methyl, (3-(tetrahydrofuran-3-yl)isoxazol-5-yl)methyl, 5-(morpholino-ethyl)-2H-tetrazol-2-yl, (4-(ethoxy-carbonyl)-1H-1,2,3-triazol-1-yl)methyl, ethyl-sulfonyl-piperazinyl-methyl, (4-(ethyl-sulfonyl-methyl)-1H-1,2,3-triazol-1-yl)methyl, methyl, methyl-piperazinyl-methyl, dimethyl-aminoethyl-amino-methyl, amino-methyl, methyl-sulfonyl-amino-methyl, methoxy-carbonyl, ethoxy-carbonyl, phenyl, hydroxy-methyl, methoxy-methyl, morpholino-methyl, phenyl-sulfonyl-methyl, dimethyl-amino-carbonyl-piperazinyl-methyl, dimethylamino-sulfonyl-piperazinyl-methyl, piperidinyl-methyl, t-butyl-carbamoyl-methyl, t-butoxy-carbonyl-amino-piperidinyl-methyl, phenyl-sulfonyl-amino-methyl, (4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl, (4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl, chloromethyl, morpholino-ethyl-piperazinyl-methyl, t-butoxy-carbonyl-amino-pyrrolidinyl-methyl, thiomorpholinomethyl, amino-pyrrolidinyl-methyl, piperazinyl-methyl, benzyl-amino-methyl, benzyloxy-methyl, 4-fluoro-benzyloxy-methyl, 2,4-difluoro-benzyloxy-methyl, (4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl, dimethyl-amino-methyl, morpholino-ureido-methyl, (4-methyl-sulfonyl-amino-methyl-1H-1,2,3-triazol-1-yl)methyl, morpholino-carbonyl, propargyl-amino-methyl, phenyl-sulfanyl-methyl, pyridinyl-methyl-amino-methyl, (4-(dimethyl-amino-methyl)-1H-1,2,3-triazol-1-yl)methyl, pyrimidinyl-piperazinyl-methyl, phenyl-pyrazonyl-methyl, (2-(tert-butoxycarbonylamino)-3-methylbutanamido)methyl, (2-amino-3-methylbutanamido)methyl, (4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl, (isopropyl-carbamoyloxy)methyl, ((t-butyl)(dimethyl)siloxy)-methyl, imidazoly-propyl-amino-methyl, (3-(2-oxopyrrolidin-1-yl)propylamino)methyl, pyrrolidinyl-ethyl-aminomethyl, pyrrolidinyl-propyl-aminomethyl, (cyclohexyl-carbamoyloxy)methyl, (benzo[d][1,3]dioxol-5-ylcarbamoyloxy)methyl, (1,3-dioxoisoindolin-2-yl)methyl, methyl-carbonyl-amino-methyl, (3-ethylureido)methyl, (tetrahydro-2H-pyran-2-yloxy)methyl, t-butoxy-carbonyl-piperazinyl-methyl, pyridinyl-ethyl-amino-methyl, methyl-carbonyl-piperazinyl-methyl, pyridinyl-piperazinyl-methyl, methoxy-carbonyl-piperazinyl-methyl, ethoxy-carbonyl-piperazinyl-methyl, piperidinyl-methyl-2H-tetrazol-2-yl, 5-chloro-pyridinyl-2-oxy-methyl, 4-phenyl-piperidinyl-methyl, 4-(pyrimidin-2-yl)-piperidinyl-methyl, (5-(pyrazin-2-yl)-2H-tetrazol-2-yl)methyl, (5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl, (5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl, 5-(6-methyl-pyridin-3-yl)-1H-tetrazol-1-yl)methyl, (5-(pyrimidin-2-yl)-2H-tetrazol-2-yl)methyl, (4-(pyrazin-2-yl)piperazin-1-yl)methyl, 4-(pyridin-2-yl)-piperidinyl-methyl, 3-t-butoxy-carbonyl-amino-pyrrolidinyl-methyl, (5-(6-chloropyridin-3-yl)-2H-tetrazol-2-yl)methyl, piperidinyl-methyl-1H-1,2,3-triazol-1-yl-methyl, 4-methyl-piperidinyl-methyl-1H-1,2,3-triazol-1-yl-methyl, 4-isopropyl-amino-methyl-1H-1,2,3-triazol-1-yl-methyl, 4-phenyl-1H-imidazol-1-yl, 1H-1,2,3-triazol-1-yl-methyl, 5-(ethoxy-carbonyl)-2H-tetrazol-2-yl, (4-(3,5-dimethylphenyl)-3-oxopiperazin-1-yl)methyl, (5-(imidazo[1,2-a]pyridin-6-yl)-2H-tetrazol-2-yl)methyl, 4-hydroxy-4-phenyl-piperidinyl-methyl, 4-hydroxy-4-(4-chloro-phenyl)-piperidinyl-methyl, (5-methyl-2-oxopyridin-1(2H)-yl)methyl, 4-methyl-pyridinyl-2-oxy-methyl, 4-ethoxy-1H-1,2,3-triazol-1-yl-methyl, morpholino-methyl-1H-1,2,3-triazol-1-yl-methyl, diethyl-amino-ethyl-1H-1,2,3-triazol-1-yl-methyl, piperidinyl-ethyl-1H-1,2,3-triazol-1-yl-methyl, piperidinyl-methyl-1H-1,2,3-triazol-1-yl-methyl, diethyl-amino-ethyl-1H-1,2,3-triazol-1-yl-methyl, isopropyl-ethyl-1H-1,2,3-triazol-1-yl-methyl, (4-((3-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl, (4-((4-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl, acetamido-phenyl-1H-1,2,3-triazol-1-yl-methyl, acetyl-1H-1,2,3-triazol-1-yl-methyl, cyclohexyl-methyl-1H-1,2,3-triazol-1-yl-methyl, thienyl-1H-1,2,3-triazol-1-yl-methyl, (2-oxo-4-(pyridin-2-yl)piperazin-1-yl)methyl, (4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl, (4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl, (4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)methyl, ethoxy-carbonyl-piperidinyl-methyl and isobutoxy-carbonyl-piperazinyl-methyl; and R_(2b) is selected from hydrogen and methyl; or R_(2a) and R_(2b) together with the carbon atom to which R_(2a) and R_(2b) are attached form carbonyl.
 4. The compound of claim 3 in which R₃, R₅, R₆ and R₇ are each independently selected from hydrogen, halo and amino.
 5. The compound of claim 4 in which R₄ is selected from: hydrogen; trifluoro-methyl; halo; hydroxy; cyano-methoxy; dimethyl-amino-propyl; cyano; cyclopropyl-methoxy; pyrazinyl-oxy optionally substituted with amino; pyridinyl-oxy; pyrimidinyl-oxy; benzoxy; phenoxy optionally substituted with methyl or cyano; ethoxy; tetrazolyl-methoxy optionally substituted with methyl; pyridazinyl-oxy; pyrazinyl-oxy; hydroxy-ethoxy; and methoxy.
 6. The compound of claim 5 in which R₈, R₉, R₁₁ and R_(12a) are each independently selected from hydrogen, halo, trifluoromethyl and methyl.
 7. The compound of claim 6 in which R₁₀ is selected from halo, cyano, methoxy, trifluoromethyl, pyridinyl-oxy, benzoyl, phenoxy, benzyl, pyridazinyl-oxy, phenyl-sulfonyl and pyrimidinyl-oxy; wherein said pyridinyl-oxy, phenyl-sulfonyl, phenoxy, benzoyl, benzyl, pyridazinyl-oxy and pyrimidinyl-oxy can be optionally substituted with 1 to 3 halo radicals.
 8. The compound of claim 1 selected from: 1-[4-(4-Chloro-phenoxy)-phenyl]-5-phenyl-pyrrolidin-2-one; 5-(4-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one; 1-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one; (S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one; 5-(2-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one; 6-(4-Amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-piperidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (R)-1-(4-(4-chlorophenoxy)phenyl)-5-phenylimidazolidine-2,4-dione; (S)-1-(4-(4-chlorophenoxy)phenyl)-5-phenylimidazolidine-2,4-dione; 1-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-fluoro-5-trifluoromethyl-phenyl)-pyrrolidin-2-one; (S)-3-[4-(4-Chloro-benzoyl)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one; (S)-3-(4-Bromo-phenyl)-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one; (S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-fluoro-5-trifluoromethyl-phenyl)-oxazolidin-2-one; (S)-3-(4-Benzyl-phenyl)-4-(3-trifluoromethyl-phenyl)-4-oxazolidin-2-one; 1-[4-(4-Chloro-phenoxy)-phenyl]-3-methyl-5-(S)-phenyl-imidazolidine-2,4-dione; 3-[4-(4-chloro-phenoxy)-phenyl]-1-methyl-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one; ethyl 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetate; (S)-ethyl 2-(3-(4-(4-chlorophenoxy)phenyl)-2,5-dioxo-4-phenylimidazolidin-1-yl)acetate; (R)-1-(4-(4-chlorophenoxy)phenyl)-3-methyl-5-phenylimidazolidine-2,4-dione; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-methyl-4-phenyloxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4,5-diphenyloxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4,5-diphenyloxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-methyl-4-phenyloxazolidin-2-one; (S)-3-(4-(4-chlorophenoxy)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one; (4S,5R)-ethyl 3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidine-5-carboxylate; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(methoxymethyl)-4-phenyloxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-phenyloxazolidin-2-one; ((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methyl isopropylcarbamate; ((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methyl cyclohexylmethylcarbamate; ((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methyl benzo[d][1,3]dioxol-5-ylcarbamate; 2-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-phenyl-oxazolidin-2-one; N-((4S,5S)-3-(4-(4-chloro-phenoxy)-phenyl)-2-oxo-4-phenyl-oxazolidin-5-ylmethyl)-methanesulfonamide; N-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methyl)acetamide; 1-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methyl)-3-ethylurea; (4S,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4-(4-chloro-phenoxy)-phenyl)-4-phenyl-oxazolidin-2-one; (4S,5R)-ethyl 3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidine-5-carboxylate; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (S)-4-(4-(4-chlorophenoxy)phenyl)-5-(3-fluorophenyl)morpholin-3-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-carboxylate; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-phenyl-5-(hydroxymethyl)oxazolidin-2-one; (2R,3S)-ethyl 4-(4-(4-chlorophenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)-5-oxomorpholine-2-carboxylate; (2S,3S)-ethyl 4-(4-(4-chlorophenoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)-5-oxomorpholine-2-carboxylate; (4S,5R)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)-3-(4-methoxyphenyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-hydroxyphenyl)oxazolidin-2-one; (5S,6R)-4-(4-(4-chlorophenoxy)phenyl)-6-((benzyloxy)methyl)-5-(3,5-difluorophenyl)morpholin-3-one; (5S,6R)-4-(4-(4-chlorophenoxy)phenyl)-5-(3,5-difluorophenyl)-6-(hydroxymethyl)morpholin-3-one); (4S,5S)-5-((2-(dimethylamino)ethylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-5-(2-(pyrrolidin-1-yl)ethylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-5-((3-(pyrrolidin-2-one)-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-5-((3-(1H-imidazol-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-5-((3-(pyrrolidin-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-5-((3-(1H-imidazol-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; tert-butyl 4-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; (4S,5S)-5-((3-(pyridin-3-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5R)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5R)-3-(4-(trifluoromethyl)phenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5S)-5-((4-acetylpiperazin-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-5-((2-(1H-imidazol-5-yl)ethylamino)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5R)-3-(4-chloro-3-methylphenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5R)-3-(4-chloro-3-fluorophenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; tert-butyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; tert-butyl 4-(((4S,5S)-3-(4-chloro-3-methylphenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; tert-butyl 4-(((4S,5S)-3-(4-chloro-3-(trifluoromethyl)phenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; (4S,5R)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5R)-5-((benzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one; tert-Butyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; Methyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; Ethyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; isobutyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; 4-((4S,5R)-4-(3-methoxyphenyl)-2-oxo-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-3-yl)benzonitrile; 4-((4S,5R)-5-((4-fluorobenzyloxy)methyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-3-yl)benzonitrile; (4S,5R)-5-((4-fluorobenzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-fluorophenyl)oxazolidin-2-one; (4S,5R)-5-((4-fluorobenzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one; (4S,5R)-5-((2,4-difluorobenzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one; 5-((4S,5R)-5-((4-methoxybenzyloxy)methyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-3-yl)pyridine-2-carbonitrile; (4S,5R)-3-(5-(4-chlorophenoxy)pyrazin-2-yl)-4-(3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((3-phenyl-1H-pyrazol-1-yl)methyl)oxazolidin-2-one; tert-butyl (R)-1-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methylcarbamoyl)-2-methylpropylcarbamate; (2R)—N-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-phenyloxazolidin-5-yl)methyl)-2-amino-3-methylbutanamide; (4S,5S)-5-((3-(pyrrolidin-1-yl)propylamino)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-methylpiperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-(3-fluorophenyl)oxazolidin-2-one; ((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl cyclohexylcarbamate; ((4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl isopropylcarbamate; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-((dimethylamino)methyl)-4-(3-fluorophenyl)oxazolidin-2-one; N-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)morpholine-4-carboxamide; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(morpholine-4-carbonyl)-4-phenyl-oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((prop-2-ynylamino)methyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((phenylthio)methyl)oxazolidin-2-one; (4S,5S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3-fluoro-phenyl)-5-{[(pyridin-3-ylmethyl)-amino]-methyl}-oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-[4-(4-Chloro-phenoxy)-phenyl]-4-(3,5-difluoro-phenyl)-5-morpholin-4-ylmethyl-oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3,5-difluorophenyl)-5-((4-methylpiperazin-1-yl)methyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((phenylsulfonyl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(chloromethyl)-4-(3-fluorophenyl)oxazolidin-2-one; (4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((4-(2-morpholinoethyl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5R)-4-(3,5-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-3-p-tolyloxazolidin-2-one; (4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one; (4S,5R)-5-((benzyloxy)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-(morpholin-4-ylmethyl)oxazolidin-2-one; (4S,5S)-5-((3-(1H-imidazol-1-yl)propylamino)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; tert-butyl (R)-1-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)pyrrolidin-3-ylcarbamate; tert-butyl 4-(((4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; (4S,5R)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(thiomorpholinomethyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(((R)-3-aminopyrrolidin-1-yl)methyl)-4-(3-fluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-((piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-5-((benzylamino)methyl)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one; (4S,5R)-3-(4-chlorophenyl)-4-(2,3-difluorophenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; (4S,5R)-5-((benzyloxy)methyl)-3-(4-chloro-3-fluorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; 4-(((4S,5S)-3-(3,4-dichlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide; 4-(((4S,5S)-3-(4-trifluoromethylphenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)-N,N-dimethylpiperazine-1-sulfamide; (4S,5S)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)-5-((piperidin-1-yl)methyl)oxazolidin-2-one; ((4S,5R)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl tert-butylcarbamate; (4S,5R)-5-((benzyloxy)methyl)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one; tert-butyl 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperidin-4-ylcarbamate; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5R)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)oxazolidin-2-one; ((4S,5R)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl cyclohexylcarbamate; N-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)benzenesulfonamide; 4-((4S,5R)-5-((benzyloxy)methyl)-4-(3-fluorophenyl)-2-oxooxazolidin-3-yl)benzonitrile; (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one; (4S,5R)-5-((4-fluorobenzyloxy)methyl)-3-(4-(trifluoromethyl)phenyl)-4-(3-fluorophenyl)oxazolidin-2-one; Ethyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; (4S,5R)-5-((4-methylbenyzyloxy)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one; (4S,5S)-3-(5-(4-chlorophenoxy)pyrazin-2-yl)-4-(3-(trifluoromethyl)phenyl)-5-(morpholinomethyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; Ethyl 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate; (4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; N-((1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methansulfonamide; (S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetonitrile; 3-(4-(4-chlorophenoxy)phenyl)-1-(4-(trifluoromethyl)benzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-[4-(4-Chloro-phenoxy)-phenyl]-1-(3,5-dimethyl-isoxazol-4-ylmethyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one; (S)-3-[4-(6-Chloro-pyridazin-3-yloxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one; (S)-3-(4-(5-chloropyridin-2-yloxy)phenyl)-4-(3-(trifluoromethyl)-phenyl)oxazolidin-2-one; (S)-1-[4-(4-Chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-imidazolidin-2-one; (R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one; (S)-3-(4-(4-chlorophenoxy)phenyl)-1-(4-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-4-(3-trifluoromethyl-phenyl)-oxazolidin-2-one; (S)-1-(6-(4-chlorophenoxy)pyridin-3-yl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-[6-(4-Chloro-phenoxy)-pyridin-3-yl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one; (S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one; (S)-1,3-Bis-[4-(4-chloro-phenoxy)-phenyl]-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-ylidene-cyanamide; (S)-3-[5-(4-Chloro-phenoxy)-pyrazin-2-yl]-1-(4-methoxy-benzyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-ylidene-cyanamide; (S)-2-(3-(5-(4-chlorophenoxy)pyrazin-2-yl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethanesulfonamide; (S)-3-[4-(4-Chloro-phenoxy)-phenyl]-1-(2-methanesulfonyl-ethyl)-4-(3-trifluoromethyl-phenyl)-imidazolidin-2-one; (S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethanesulfonamide; 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetic acid; 1-((1H-tetrazol-5-yl)methyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-propylacetamide; 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(piperidin-1-yl)acetamide; 2-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetamido)acetic acid; 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(2-hydroxyethyl)acetamide; 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(2-(dimethylamino)ethyl)acetamide; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one; 1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-imine; 1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidine-2-thione; 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl methanesulfonate; 1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one oxime; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(2-hydroxyethylamino)ethyl)-4-(3-(trifluoromethyl)-phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-morpholinoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(4-methylpiperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl carbamate; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylamino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(piperidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(piperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one; (4R,5S)-methyl 1-(4-(4-chlorophenoxy)phenyl)-2-oxo-5-phenylimidazolidine-4-carboxylate; 1-(4-chlorobenzyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 1-benzyl-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(3-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(4-methoxyphenyl)-4-(3-(trifluoromethyl)phenyl)-imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-morpholino-2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-((2S,6R)-2,6-dimethylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 1-(2-aminoethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)-1,1-dimethylurea; N-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)morpholine-4-carboxamide; N-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)methanesulfonamide; 3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-2-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-3-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-4-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-tosyl-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; (S)-3-(4-(4-chlorophenoxy)phenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; (R)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-((R)-2-methylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-((S)-2-methylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; (S)-3-(4-(4-chlorophenoxy)phenyl)-1-(3-(methylsulfonyl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; 3-(4-(4-chlorophenoxy)phenyl)-1-(3-morpholinopropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-morpholinoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; N-(3-(4-(4-chlorophenoxy)phenyl)-1-(2-((S)-2-methylmorpholino)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; N-(3-(4-(4-chlorophenoxy)phenyl)-1-(3-(methylsulfonyl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; (R)-1-(4-(4-chlorophenoxy)phenyl)-5-phenylpyrrolidin-2-one; (R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one; (R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)pyrrolidin-2-one; (R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-methoxyphenyl)pyrrolidin-2-one; (R)-1-(4-(4-chlorophenylsulfonyl)phenyl)-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one; (R)-1-(4-(4-chlorophenylsulfonyl)phenyl)-5-(3-methoxyphenyl)pyrrolidin-2-one; (R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one; (R)-1-(4-(4-chlorophenoxy)phenyl)-2-(3-(trifluoromethyl)phenyl)pyrrolidine; (R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)pyrrolidin-2-one; (R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-one; (R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(4-(4-chlorophenylsulfonyl)phenyl)pyrrolidin-2-one; (R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-hydroxyphenyl)pyrrolidin-2-one; (R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-cyanomethoxyphenyl)pyrrolidin-2-one; (R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)pyrrolidin-2-one; (3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-3-allyl-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one; (3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-3-allyl-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one; (R)-1-(4-(4-chlorophenoxy)phenyl)-3,3-diallyl-5-(3-(trifluoromethyl)phenyl)pyrrolidin-2-one; (R)-5-(3-((1-methyl-1H-tetrazol-5-yl)methoxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-one; (R)-5-(3-(2-methyl-2H-tetrazol-5-yl)methoxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-one; (3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-hydroxyethyl)pyrrolidin-2-one; (3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-hydroxyethyl)pyrrolidin-2-one; (R)-2-(3-(1-(4-(4-chlorophenoxy)phenyl)pyrrolidin-2-yl)phenoxy)ethanol; (3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(3-hydroxypropyl)pyrrolidin-2-one; (3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(3-hydroxypropyl)pyrrolidin-2-one; (R)-1-(4-chlorophenyl)-5-(3-methoxyphenyl)pyrrolidin-2-one; (R)-1-(4-chlorophenyl)-5-(3-(pyridazin-3-yloxy)phenyl)pyrrolidin-2-one; (R)-1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)pyrrolidin-2-one; (R)-5-(3-(2-hydroxyethoxy)phenyl)-1-(4-chlorophenyl)pyrrolidin-2-one; (3R,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-(methylsulfonyl)ethyl)pyrrolidin-2-one; (3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(2-(methylsulfonyl)ethyl)pyrrolidin-2-one; (S)-methyl 5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-carboxylate; (S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine; (R)-5-(3-(cyanomethoxy)phenyl)-1-(4-chlorophenyl)pyrrolidin-2-one; (S)-methyl 5-(4-chlorophenyl)-4-(3-hydroxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-carboxylate; (S)-3-(2-(4-chlorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-yl)phenol; (S)-2-(4-chlorophenyl)-1,1-dioxo-5-(pyrazin-2-yl)-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine; (S)-2-(4-chlorophenyl)-1,1-dioxo-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine; (S)—N,N-bis(4-methoxybenzyl)-3-(5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)propanesulfamide; (S)-2-(4-chlorophenyl)-1,1-dioxo-5-(3-(methylsulfonyl)propyl)-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine; (3S,5R)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)-3-(3-(methylsulfonyl)propyl)pyrrolidin-2-one; (S)-2-(5-(4-chlorophenyl)-4-(3-(cyanomethoxy)phenyl)-1,1,-dioxo-1,2,5-thiadiazolidin-2-yl)acetonitrile; (S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-(pyrazin-2-yl)-1,2,5-thiadiazolidine; (S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-(pyridazin-3-yl)-1,2,5-thiadiazolidine; (S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-phenyl-1,2,5-thiadiazolidine; (S)-2-(5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)acetonitrile; (S)-2-(4-chlorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-5-((3,5-dimethylisoxazol-4-yl)methyl)-1,2,5-thiadiazolidine; (S)-methyl 3-(5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)methyl)isoxazole-5-carboxylate; (S)-3-((5-(4-chlorophenyl)-4-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)methyl)-1,2,4-oxadiazole; (S)-3-(2-(4-chlorophenyl)-1,1-dioxo-5-phenyl-1,2,5-thiadiazolidin-3-yl)phenol; (S)-3-(5-(4-chlorophenyl)-1,1-dioxo-4-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidin-2-yl)propane-1-sulfonamide; (S)-2-(4-chlorophenyl)-1,1-dioxo-5-phenyl-3-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidine; (S)-4-(5-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)-1,2,5-thiadiazolidin-2-yl)methyl)-3,5-dimethylisoxazole; (S)-2-(4-chlorophenyl)-5-(4-fluorophenyl)-3-(3-methoxyphenyl)-1,1-dioxo-1,2,5-thiadiazolidine; (R)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-(cyanomethoxy)phenyl)pyrrolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)oxazolidin-2-one; (S)-methyl 5-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-dioxide-2-carboxylate; (S)-2-(4-(4-chlorophenoxy)phenyl)-3-(3-methoxyphenyl)-1,2,5-thiadiazolidine-1,1-dioxide; (S)-4-(3-(m-tolyloxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-4-(3-(3-cyanophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-4-(3-(2-chlorophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-4-(3-(4-methoxyphenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-4-(3-(2-cyanophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-4-(3-(4-cyanophenoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(pyridin-2-yloxy)phenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(pyrimidin-2-yloxy)phenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-ethoxyphenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(cyclopropylmethoxy)phenyl)oxazolidin-2-one; (S)-4-(3-(3-(dimethylamino)propoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-4-(3-(cyanomethoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-4-(3-(2-hydroxyethoxy)phenyl)-3-(4-chlorophenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)oxazolidin-2-one; 5-(3-(benzyloxy)phenyl)-1-(4-(4-chlorophenoxy)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-4-(3-(benzyloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-4-(3-hydroxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-2-yloxy)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; 4-(3-(2-cyanophenoxy)phenyl)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 5-(3-(benzyloxy)phenyl)-1-(4-chlorophenyl)imidazolidin-2-one; 4-(3-(benzyloxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; 4-(3-(2-cyanophenoxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrimidin-2-yloxy)phenyl)imidazolidin-2-one; 3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-2-yloxy)phenyl)imidazolidin-2-one; 3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-3-yloxy)phenyl)imidazolidin-2-one; 3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-4-yloxy)phenyl)imidazolidin-2-one; 3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one; 4-(3-(4-methoxyphenoxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 4-(3-(5-aminopyrazin-2-yloxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; 3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrimidin-5-yloxy)phenyl)imidazolidin-2-one; (4S,5S)-1-(3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-N-(piperidin-1-yl)-1H-1,2,3-triazole-4-carboxamide; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-fluorophenyl)-5-(morpholinomethyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(morpholinomethyl)-4-(3-(trifluoromethyl)phenyl)oxazolidin-2-one; (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-5-(morpholinomethyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-(ethylsulfonylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)oxazolidin-2-one; ethyl 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperidine-4-carboxylate; tert-butyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1,4-diazepane-1-carboxylate; (4S,5S)-3-(4-chlorophenyl)-5-((4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; ethyl 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate; (4S,5S)-3-(4-chlorophenyl)-5-((4-(ethylsulfonyl)piperazin-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-cyclopentyl-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-5-((4-acetyl-1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-isopentyl-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(2-methoxyphenyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((5-(2-(diethylamino)ethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(2-(piperidin-1-yl)ethyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-((diethylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-(morpholinomethyl)-4-(3-(pyrazin-2-yloxy)phenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-((isopropylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(ethylsulfonyl)piperazin-1-yl)methyl)oxazolidin-2-one; ethyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; (4S,5S)-3-(4-chlorophenyl)-5-((4-(cyclohexylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-5-((4-acetyl-1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-5-((4-(azepan-1-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-((4-methylpiperidin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; tert-butyl 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)pyrrolidin-3-ylcarbamate; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-ethoxy-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((5-(6-chloropyridin-3-yl)-2H-tetrazol-2-yl)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-phenylpiperidin-1-yl)methyl)oxazolidin-2-one; (4S,5R)-3-(4-chlorophenyl)-5-((5-chloropyridin-2-yloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(pyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; ethyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-ethoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; ethyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyrimidin-2-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyrazin-2-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyridin-2-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-methyl-2-oxopyridin-1(2H)-yl)methyl)oxazolidin-2-one; (4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-methylpyridin-2-yloxy)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(imidazo[1,2-a]pyridin-6-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((3-oxo-4-(pyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(pyrazin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-(3,5-dimethylphenyl)-3-oxopiperazin-1-yl)methyl)oxazolidin-2-one; (S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-1-(pyrazin-2-yl)imidazolidin-2-one; N-(3-(1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)acetamide; (4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((4-(3-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((4-(5-methyl-1H-pyrazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; ethyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazine-1-carboxylate; benzyl 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2-oxopiperidine-4-carboxylate; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; 4-(1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-4-yl)benzonitrile; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-((tetrahydrofuran-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-fluorophenyl)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(1-methyl-1H-imidazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((4-ethoxy-1H-1,2,3-triazol-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(3-methyl-1,2,4-oxadiazol-5-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-phenyl-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; ethyl 2-(2-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazol-5-yl)acetate; (4S,5S)-3-(4-chlorophenyl)-5-((5-(2-hydroxyethyl)-2H-tetrazol-2-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(2-morpholinoethyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((3-(tetrahydrofuran-3-yl)isoxazol-5-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; tert-butyl 4-((4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)piperidine-1-carboxylate; ethyl 2-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazole-5-carboxylate; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-phenyl-1H-imidazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-((tetrahydrofuran-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-((piperidin-1-yl)methyl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; tert-butyl 4-(2-(((4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)-2H-tetrazol-5-yl)piperidine-1-carboxylate; tert-butyl 4-(1-(((4S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl)-1H-tetrazol-5-yl)piperidine-1-carboxylate; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((4-phenyl-1H-imidazol-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(pyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)-4-(3-(trifluoromethoxy)phenyl)oxazolidin-2-one; ethyl 4-(((4S,5S)-3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethoxy)phenyl)oxazolidin-5-yl)methyl)piperazine-1-carboxylate; (4S,5S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-isopropoxyphenyl)-5-((5-(6-methylpyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; 6-(4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)piperazin-1-yl)pyridine-3-carbonitrile; (4S,5S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-5-((5-(6-methoxypyridin-3-yl)-2H-tetrazol-2-yl)methyl)oxazolidin-2-one; (4S,5R)-5-((5-cyanopyridin-2-yloxy)methyl)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)oxazolidin-2-one; 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1-(6-methoxypyridin-3-yl)piperazin-2-one; (4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-5-((4-(6-methoxypyridin-2-yl)piperazin-1-yl)methyl)oxazolidin-2-one; 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-1-(6-methoxypyridin-2-yl)piperazin-2-one; tert-butyl 4-(((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)methyl)-3-oxopiperazine-1-carboxylate; (4S,5S)-3-(4-chlorophenyl)-5-((4-(4-fluoropyridin-2-yl)piperazin-1-yl)methyl)-4-(3-methoxyphenyl)oxazolidin-2-one; ethyl 3-((4S,5S)-3-(4-chlorophenyl)-4-(3-methoxyphenyl)-2-oxooxazolidin-5-yl)propanoate; (4S,5S)-3-(4-chlorophenyl)-5-((3-(diethylamino)pyrrolidin-1-yl)methyl)-4-(3-fluorophenyl)oxazolidin-2-one; tert-butyl 1-(((4S,5S)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)pyrrolidin-3-ylmethylcarbamate; (S)-3-(4-chlorophenyl)-1-((5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(pyridin-3-ylmethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(4-methoxybenzyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethanesulfonamide; (S)-3-(4-chlorophenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(3-hydroxypropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-propylacetamide; (S)-3-(4-chlorophenyl)-1-(2-oxo-2-(piperidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(piperidin-1-yl)acetamide; (S)-tert-butyl 4-(2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)acetyl)piperazine-1-carboxylate; (S)-3-(4-chlorophenyl)-1-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-((5-(4-chlorophenyl)oxazol-2-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-methyl 3-((3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)methyl)isoxazole-5-carboxylate; (S)-3-(4-chlorophenyl)-1-(2-morpholinoethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(4-hydroxypiperidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(3-morpholinopropyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-1-((5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(piperidin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(morpholinosulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propane-1-sulfonamide; (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(2-hydroxyethyl)ethanesulfonamide; (S)-3-(4-chlorophenyl)-1-((6-morpholinopyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-((6-(piperidin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-1-((6-(bis(2-hydroxyethyl)amino)pyridin-3-yl)methyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-((6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)methyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (4S)-3-(4-chlorophenyl)-1-(3-(3-(diethylamino)pyrrolidin-1-yl)propyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-1-(2-(5-tert-butyl-1,2,4-oxadiazol-3-yl)ethyl)-3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(morpholinosulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propane-1-sulfonamide; (S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N-(2-hydroxyethyl)ethanesulfonamide; (S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)-N,N-bis(2-hydroxyethyl)ethanesulfonamide; (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-methoxyphenyl)imidazolidin-2-one; (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)imidazolidin-2-one; (S)-2-(3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-2-oxoimidazolidin-1-yl)ethanesulfonamide; (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(2-hydroxyethoxy)phenyl)imidazolidin-2-one; (S)-2-(3-(4-(4-chlorophenoxy)phenyl)-4-(3-(2-hydroxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)ethanesulfonamide; (S)—N-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethylsulfonyl)acetamide; (S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; tert-butyl 4-((2-((S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-2-oxoimidazolidin-1-yl)ethyl)sulfonyl)piperazine-1-carboxylate; (S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)-1-(2-((piperazin-1-yl)sulfonyl)ethyl)imidazolidin-2-one; (S)-1-(4-chlorophenyl)-5-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(pyridazin-3-yloxy)phenyl)oxazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(morpholino sulfonyl)ethyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(pyridazin-3-yloxy)phenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)imidazolidin-2-one; (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-1-yl)ethanesulfonamide; (S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(morpholino sulfonyl)ethyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)imidazolidin-2-one; (S)-2-(3-(4-chlorophenyl)-4-(3-(2-hydroxyethoxy)phenyl)-2-oxoimidazolidin-1-yl)ethanesulfonamide; (S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-1-yl)ethanesulfonamide; (S)-1-(5-(4-chlorophenoxy)pyrazin-2-yl)-5-(3-methoxyphenyl)imidazolidin-2-one; (S)-3-(5-(4-chlorophenoxy)pyrazin-2-yl)-4-(3-methoxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; (S)-1-(2-(azetidin-1-ylsulfonyl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-1-(2-(azetidin-1-ylsulfonyl)ethyl)-3-(4-chlorophenyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one; (S)-3-(4-(4-chlorophenoxy)phenyl)-1-(4-(methylsulfonyl)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-one; (S)-4-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)benzenesulfonamide; (S)-4-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-1-yl)benzenesulfonamide; (S)-methyl 3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propanoate; (S)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-3-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)propanamide; (S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)sulfamide; (S)-3-(4-chlorophenyl)-1-(pyrazin-2-yl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)methanesulfonamide; (S)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyridin-2-yloxy)phenyl)imidazolidin-2-one; (4S)-3-(4-(4-chlorophenoxy)phenyl)-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-1-(2-(1,3-dioxan-2-yl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(4-(4-chlorophenoxy)phenyl)-1-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 3-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl)oxazolidin-2-one; 1-(2-(1H-pyrazol-1-yl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; 1-(2-(1H-imidazol-1-yl)ethyl)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one; (S)-1-(4-(4-chlorophenoxy)phenyl)-2-(nitromethylene)-5-(3-(trifluoromethyl)phenyl)imidazolidine; (S)—N-(1-(4-chlorophenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)methanesulfonamide; (S)-3-(4-chlorophenyl)-4-(3-(6-methylpyridin-3-yloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; (S)-1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-1-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)urea; (S)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-2-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-1-yl)ethanesulfonamide; (S)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)-1-(2-(pyrrolidin-1-ylsulfonyl)ethyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(morpholinosulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(4-methylpiperazin-1-ylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-3-(4-chlorophenyl)-1-(2-(piperazin-1-ylsulfonyl)ethyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)—N-(1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-ylidene)methanesulfonamide; (S)—N-(1-(4-chlorophenyl)-5-(3-(2-hydroxyethoxy)phenyl)imidazolidin-2-ylidene)methanesulfonamide; (S)—N-(1-(4-chlorophenyl)-5-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-ylidene)sulfamide; (S)—N-(1-(4-chlorophenyl)-5-(3-(pyridazin-3-yloxy)phenyl)imidazolidin-2-ylidene)methanesulfonamide; (S)-1-(2-(1,3-dioxan-2-yl)ethyl)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-3-(4-(4-chlorophenoxy)phenyl)-4-(3-methoxyphenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; (S)-3-(3-(4-chlorophenyl)-2-oxo-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-1-yl)propanamide; (S)—N-(3-(4-(4-chlorophenoxy)phenyl)-1-cyano-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-ylidene)cyanamide; (S)-1-(2-(1H-1,2,4-triazol-3-yl)ethyl)-3-(4-chlorophenyl)-4-(3-(pyrazin-2-yloxy)phenyl)imidazolidin-2-one; (S)-3-(3-(3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)-2-oxoimidazolidin-4-yl)phenoxy)pyrazine-2-carbonitrile; (S)-3-(4-chlorophenyl)-4-(3-(3-ethylpyrazin-2-yloxy)phenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one; and (S)-4-(3-(5-aminopyrazin-2-yloxy)phenyl)-3-(4-chlorophenyl)-1-(2-(methylsulfonyl)ethyl)imidazolidin-2-one.
 9. A method of treating a disease mediated by the Cannabinoid-1 receptor comprising administration of to a patient in need of such treatment of a therapeutically effective amount of a compound of claim
 1. 10. The method according to claim 9 wherein the disease mediated by the Cannabinoid-1 receptor is an eating disorder associated with excessive food intake.
 11. The method according to claim 10 wherein the eating disorder associated with excessive food intake is selected from obesity, bulimia nervosa, and compulsive eating disorders.
 12. The method according to claim 11 wherein the eating disorder associated with excessive food intake is obesity.
 13. A method of preventing obesity in a person at risk for obesity comprising administration to said person of about 0.001 mg to about 100 mg per kg of a compound selected from a compound of claim
 1. 14. A composition comprising a pharmaceutically acceptable carrier and a compound selected from a compound of claim
 1. 15. The use of a compound for the manufacture of a medicament useful for the treatment of a disease mediated by the Cannabinoid-1 receptor in a human patient in need of such treatment, said compound being selected from a compound of claim
 1. 16. The use according to claim 15 wherein the disease mediated by the Cannabinoid-1 receptor is selected from: metabolic disorders as well as conditions associated with metabolic disorders including obesity, bulimia nervosa, compulsive eating disorders, diabetes, arteriosclerosis, hypertension, osteoporosis, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders, and hyperlipidemic conditions; or psychiatric disorders such as substance abuse, psychosis, depression, anxiety, stress, epilepsy, mania and schizophrenia; or cognitive disorders such as dementia including Alzheimer's disease, memory deficits, short term memory loss and attention deficit disorders; or neurodegenerative disorders such as Parkinson's Disease, cerebral apoplexy and craniocerebral trauma, hypotension, catabolism in connection with pulmonary dysfunction and ventilator dependency; or cardiac dysfunction including valvular disease, myocardial infarction, cardiac hypertrophy and congestive heart failure); or the overall pulmonary dysfunction, transplant rejection, rheumatoid arthritis, migraine, neuropathy, multiple sclerosis, Guillain-Barre syndrome, the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, inflammatory bowel disease, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, psoriasis, osteoporosis, asthma, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic rhinitis, ischemic or reperfusion injury, head trauma and movement disorders.
 17. The use according to claim 16 wherein the disease mediated by the Cannabinoid-1 receptor is an eating disorder associated with excessive food intake.
 18. The use according to claim 17, wherein the eating disorder associated with excessive food intake is selected from obesity, bulimia nervosa, and compulsive eating disorders.
 19. The use according to claim 18 wherein the eating disorder associated with excessive food intake is obesity.
 20. The use of a compound according to claim 1 for the manufacture of a medicament for the prevention of obesity in a person at risk therefor.
 21. A process of preparing a compound of claim 1 with a greater than 80% yield wherein any aryl is bonded directly to a group selected from an amide, a carbamate and a nitrogen containing heterocycle forming a compound of Formula I; which process comprises: reacting an aryl-halide with an amide, a carbamate or a nitrogen containing heterocycle in the presence of a copper catalyst; cesium fluoride; a solvent; at a temperature of less than or equal to 100° C. for less than or equal to 24 hours.
 22. The process of claim 21 in which the copper catalyst is copper iodide.
 23. The process of claim 22 in which the solvent is selected from THF, CAN, DMSO, DME, DMF, Dioxane, toluene and EtOAc.
 24. The process of claim 23 in which the temperature is less than or equal to 75° C.
 25. The process of claim 24 in which the temperature is less than or equal to 50° C.
 26. The process of claim 25 in which the temperature is less than or equal to 25° C.
 27. The process of claim 26 in which the reaction takes between 18 and 24 hours. 